Aminoquinazoline derivatives as P2X3 inhibitors

Abstract

The present invention relates to compounds of formula I which inhibit P2X purinoceptor 3; in particular, the invention relates to compounds which are aminoquinazoline derivatives, methods for preparing such compounds, pharmaceutical compositions containing them and their therapeutic use. The compounds of the present invention may be useful in the treatment of a number of conditions associated with P2X3 receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

Description

[Technical Field]

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

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

[0003] Background of the Invention P2X receptors are cell surface ion channels activated by extracellular adenosine 5-triphosphate (ATP). The P2X receptor family is a trimer assembly consisting of seven distinct subunit subtypes (P2X1-7) that assemble as homomeric and heteromeric channels. All subunits share a common morphology of an intracellular terminal, two transmembrane helices that form the ion channel, and a large extracellular domain containing an ATP-binding site. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X 2 / 3 and P2X 1 / 5The channels have been fully characterized after heterologous expression. P2X receptors are abundantly distributed, and functional responses are found in neurons, glia, epithelium, endothelium, bone, muscle, and hematopoietic tissue. In smooth muscle, P2X receptors respond to ATP released from sympathetic motor neurons (e.g., in ejaculation). In sensory nerves, they are involved in the initiation of afferent signaling in several viscera (e.g., bladder, intestine) and play a crucial role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles of ATP signaling mediated by P2X receptors may be present in the neurogenic pituitary gland, ductal glands, airway epithelium, kidney, bone, and hematopoietic tissue. (RA. North: Molecular Physiology of P2X Receptors; Physiol Rev, Vol 82, Oct 2002). All P2X receptors are Na+ and Ca+ ion-permeable, non-selective cation channels activated by ATP; however, the pharmacology of receptor subtypes varies in terms of 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, the P2X3 receptor has been reported at the mRNA level in the heart and spinal cord, and at the protein level in the RG, intestines (myenteric plexus neurons), bladder (urothelium and suburothelium), and dental pulp (Garcia-Guzman M et al: Molecular characterization and pharmacological properties of the human P2X3purinoceptor: Brain Res Mol Brain Res. 1997;47(1-2):59-66).

[0005] The role of P2X3 receptors in airway sensory nerve function is similar to that of somatic nociception-mediated receptors (Undem BJ and Nassenstein C: Airway nerves and dyspnea associated with inflammatory airway disease, Respir Physiol Nerobiol 167: 36-44, 2009). This similarity has led to the hypothesis that P2X3 receptors may be involved in symptoms of airway dysfunction, including cough and bronchial reactivity (Ford AP: In pursuit of P2X3antagonists: novel therapeutics for chronic pain and afferent sensitization, Purinergic signal 8 (suppl 1):3-26, 2012; North RA, Jarvis MF P2X Receptors as Drug Targets; Mol Pharmacol, 83:759-769, 2013). The P2X3 subunit is also co-localized in many neurons, particularly in the DRG, inferior ganglia, nucleus tractus solitarius, 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 channels play an important role in the extension of joint pain hypersensitivity in arthritis (Teixeira JM et al: P2X3 and P2X 2 / 3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis, Mol Neurobiol Oct;54(8):6174-6186, 2017).

[0008] P2X3 may also be a potential target for therapeutic treatment of bladder pain. It has also been proposed as an analgesic target for the treatment of 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 expression has also been associated with poor recurrence-free survival in hepatocellular carcinoma patients, and P2X3 has been identified as a potential therapeutic target (Maynard JP et al: P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients Oncotarget Dec 1;6(38):41162-79, 2015).

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

[0011] ATP promotes citrate-induced and histamine-induced reactions in preclinical models and can be attenuated 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). https: / / www.ncbi.nlm.nih.gov / pubmed / 16935279 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 prospects for treating chronic cough with P2X3 antagonists were first recognized by Ford and Undem (Ford AP, Undem BJ: The therapeutic promise of ATP antagonism, P2X3 receptors in respiratory and urological disorders, Front Cell Neurosci, Dec 19;7:267, 2013). P2X3 is expressed by afferent airway nerves and mediates hypersensitivity to 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 mostly P2X 2 / 3 NTPDase2 is an important neurotransmitter in the taste system that acts via heteromultimeric receptors. Consequently, disruption of taste function can be an unintended consequence of therapeutic trials using purine-mediated P2X3 antagonists for pain, chronic cough, and other conditions (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] Various compounds, P2X3 and / or P2X 2 / 3 It is listed in the literature as an inhibitor.

[0015] WO2017058645 (Afferent Pharmaceuticals INC) discloses the use of an effective amount of a disclosed compound of a diaminopyrimidine P2X3 / P2X 2 / 3 antagonist in the treatment of disorders including cough, chronic cough and cough impulse, including cough associated with a respiratory disease or disorder, by administering the compound. However, aminoquinazoline derivatives are not disclosed.

[0016] WO2017011729 (Patara Pharma LLC) discloses the use of cromolyn or a pharmaceutically acceptable salt thereof and a P2X3 and / or P2X 2 / 3 receptor antagonist as an antitussive for the treatment of lung diseases and conditions.

[0017] WO2016091776 (Evotec AG) discloses a 1,3-thiazol-2-yl substituted benzamide compound that inhibits the P2X3 receptor, a pharmaceutical composition containing such a compound, and the use of the compound for the treatment of several disorders including respiratory diseases.

[0018] WO2016088838 (Shionogi) discloses a purine derivative compound having novel P2X3 and / or P2X 2 / 3 receptor antagonistic effects.

[0019] WO2016084922 (Shionogi) discloses a triazine derivative compound having novel P2X3 and / or P2X 2 / 3 receptor antagonistic effects.

[0020] WO2008123963 (Renovis) relates to a condensed heterocyclic compound of the tetrahydropyrido[4,3-d]pyrimidine group and a pharmaceutical composition containing such a compound. Methods for the prevention and / or treatment of several disorders such as neurodegenerative disorders, pain, asthma, autoimmune disorders, etc. by administering the disclosed compound are also provided.

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

[0022] WO2010033168(Renovis) is a P2X purinergic receptor and more specifically a P2X3 receptor and / or P2X 2 / 3 We disclose a series of phenyl or pyridyl-substituted benzamides that are said to be useful in treating receptor antagonist-related diseases. However, aminoquinazoline derivatives are not disclosed.

[0023] WO2009110985 (Renovis) relates to phenyl and pyridyl-substituted benzamide compounds and pharmaceutical compositions containing such compounds, but due to the presence of thiazole-substituted benzamides, these compounds differ from the compounds of the present invention.

[0024] WO2008000645 (Roche) is useful for the treatment of urogenital, pain, gastrointestinal and respiratory diseases, conditions and disorders, P2X3 and / or P2X 2 / 3 We disclose tetrazole-substituted arylamides that act as receptor antagonists.

[0025] Despite the prior art described above, novel aminoquinazoline compounds, particularly those selectively acting on P2X3 receptors, remain needed for the treatment of P2X3 receptor-related diseases, especially in many therapeutic areas such as respiratory diseases. [Overview of the project] [Problems that the invention aims to solve]

[0026] It is noteworthy that prior art neither describes nor suggests any aminoquinazoline derivative compound of general formula (I) of the present invention that would solve the above-mentioned need. [Means for solving the problem]

[0027] Summary of the Invention The present invention relates to formula (I) [ka] [In the formula, X is selected from S, SO2, SO, or O; Z is selected from the group consisting of heteroaryls and aryls, where each such heteroaryl and aryl may be substituted with one or more groups selected from (C1-C3)alkyl-, halo, and (C1-C6)haloalkyl-; R1 is H or (C1-C4) alkyl; R2 is a heteroaryl (C1-C4)alkyl-, where either such alkyl or heteroaryl may be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl, and halo; R stands for (C1-C6)alkyl-, (C1-C6)alkyl-CN, (C1-C6)haloalkyl, -NR A R B , (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, (C3-C8)heterocycloalkyl-, (C3-C8)heteroaryl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-, R A O-(C1-C6)alkyl-O-(C1-C6)alkyl-, R A NH-C(O)-(C1-C4)alkyl-, R A R B NC(O)-(C1-C4)alkyl-, R A Selected from the group consisting of OC(O)(C1-C6)alkyl-, Here, all of these heterocycloalkyl groups are either unsubstituted or OH, -C(O)R A , -C(O)OR A , substituted with one or more groups selected from (C1-C6)haloalkyl, -NH-C(O)R1 and oxo; All of these cycloalkyls are -C(O)OR Aand are substituted with one or more groups selected from (C1-C6) haloalkyl-, Each of these heteroaryls may be substituted with one or more groups selected from (C1-C6)alkyl-, -OH, and (C3-C6)cycloalkyl-; R A and R B In each case, it is independently H or (C1-C6)alkyl-, (C1-C6)haloalkyl-, -OR1, -SO2R C and selected from the group consisting of (C3-C6) cycloalkyl groups, where such cycloalkyl groups may be substituted with one or more -C(O)OR1 groups or otherwise. R A and R B These may, together with the nitrogen atom to which they are bonded, form a five- or six-membered saturated heterocyclic monocyclic ring system containing a further heteroatom, which may optionally be nitrogen or oxygen, and which may optionally be substituted with one or more groups selected from halo, -OR1; R C is an arrow; However, R is (C1-C6) alkyl- or unsubstituted (C3-C8) heterocycloalkyl- only when X is S or SO. Regarding the compounds.

[0028] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone, in combination with one or more other active ingredients, and mixed with one or more pharmaceutically acceptable carriers or additives.

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

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

[0031] In a further embodiment, the present invention relates to compounds of formula (I) for use in the prevention and / or treatment of respiratory diseases, including cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, postviral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm. [Modes for carrying out the invention]

[0032] Detailed description of the invention Unless otherwise specified, the compounds in terminology formula (I) include stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0033] The term "pharmaceutically acceptable salt" as used herein refers to a derivative of the compound of formula (I) in which the parent compound has been appropriately modified, if present, by the conversion of a free acidic or basic group to a corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0034] Suitable examples of the salt may therefore include inorganic or organic acid addition salts of basic groups such as amino groups, and inorganic or organic basic addition salts of acidic groups such as carboxylic acid groups.

[0035] The terms "halogen" or "halogen atom" as used herein include fluorine, chlorine, bromine, and iodine atoms, preferably chlorine or fluorine.

[0036] The term “(C x -C y A alkyl group (where x and y are integers) is a linear or branched alkyl group having x to y carbon atoms. For example, when x is 1 and y is 6, this term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

[0037] The term used here is "(C x -C y)Alkylene (where x and y are integers) is a C with a total of two unsatisfied valences, such as a divalent methylene radical. x -C y This refers to an alkyl group.

[0038] The expression “(C x -C y A "haloalkyl" (where x and y are integers) is defined as a "C" as defined above, in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. x -C y This refers to the "alkyl" group.

[0039] Therefore, the said "(C x -C y Examples of "haloalkyl" groups may include halogenated, polyhalogenated, and groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl or difluoromethyl and trifluoroethyl groups.

[0040] Similarly, the terms "(C1-C6) hydroxyalkyl" or "(C1-C6) aminoalkyl" refer to the "(C1-C6) alkyl" group defined above, in which one or more hydrogen atoms are replaced by one or more hydroxy(OH) or amino groups, respectively. Examples include hydroxymethyl, aminomethyl, and dimethylaminopropyl, respectively.

[0041] In this specification, unless otherwise specified, aminoalkyl refers to one or more amino groups (-NR A R B It contains alkyl groups substituted with (i.e., "(C1-C6) alkyl" groups). Therefore, an example of an aminoalkyl group is R A R B These are mono-aminoalkyl groups such as N-(C1-C6) alkyl groups.

[0042] The term “(C x -C yA cycloalkyl group (where x and y are integers) is a saturated cyclic hydrocarbon group containing the specified number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0043] The term "aryl" refers to a monocyclic carbocyclic system having six aromatic ring atoms. A suitable example of an aryl monocyclic system is phenyl.

[0044] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic radical containing one or more heteroatoms selected from S, N, and O, including radicals having two such monocyclic rings condensed by a common bond, or one such monocyclic ring and one monocyclic aryl ring. Suitable examples of 5,6-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and triazinyl.

[0045] The term "heterocyclyl" or "heterocyclic" refers to saturated monocyclic, dicyclic, or tricyclic non-aromatic radicals containing one or more heteroatoms selected from S, N, and O. In the case of bicyclic heterocyclic systems, condensed, spirocyclic, and bridging bicyclic systems are included within the scope of this term.

[0046] The term “(C x -C y A heterocycloalkyl (where x and y are integers) is a saturated or partially unsaturated monocyclic (C) molecule in which at least one ring carbon atom is replaced by at least one heteroatom (e.g., N, S, or O) or can support an oxo(=O) substituent. x -C y(C) refers to a cycloalkyl group. The heterocycloalkyl group (i.e., a heterocyclic radical or group) may be further substituted at available positions on the ring, i.e., carbon atoms or heteroatoms available for substitution. Substitutions of carbon atoms include spirodisubstitutions and substitutions of two adjacent carbon atoms, and in either case, a further condensed 5-6 membered heterocyclic ring is formed. x -C y Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperadinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydropyridinyl, tetrahydrothiophenyl, azetidinyl, oxetanyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidine-2-onyl, and dihydropyrrolyl groups.

[0047] Specific examples of the heterocyclic radical include tetrahydrothiophene 1,1-dioxide, 3,3-difluoropyrrolidinyl, 1-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl.

[0048] The terms "aryloxyl" and "aryl(C1-C6)alkoxyl," as well as "heteroaryloxyl" and "heteroaryl(C1-C6)alkoxyl," refer to aryl or heteroaryl groups linked via oxygen crosslinking and linear aryl-alkoxyl or heteroaryl-alkoxyl groups. Examples of such groups are phenyloxy, benzyloxy, and pyridinyloxy, respectively.

[0049] The term "aryl(C1-C6)alkyl" refers to an aryl ring linked to a linear or branched alkyl group having 1 to 6 carbon atoms, such as phenylmethyl (i.e., benzyl), phenylethyl, or phenylpropyl.

[0050] Terminology (C z -C k) Heterocycloalkyl-(C x -C y An alkyl group (where z and k are integers) is a heterocyclic ring linked to a chain or branched alkyl group having x to y carbon atoms.

[0051] 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 chain or branched alkyl group having x~y carbon atoms.

[0052] The expression "ring system" is aryl, (C3-C 10 This refers to monocyclic, bicyclic, or polycyclic ring systems that may be saturated, partially unsaturated, or unsaturated, such as cycloalkyl, (C3-C6) heterocycloalkyl, or heteroaryl rings.

[0053] The terms “group,” “radical,” “fragment,” or “substituent” are synonymous and are intended to refer to a bond or other fragment or a fragment of a functional group molecule that can be bonded to a molecule. For example, “heterocyclic radical” as used herein means a monocyclic or dicyclic saturated or partially saturated heterocyclic moiety (group, radical), preferably a 4- to 11-membered monocyclic radical, wherein at least one further ring carbon atom in the heterocyclic radical may be replaced by at least one further heteroatom independently selected from N, S, or O and / or may have an oxo(=O) substituent, and the heterocyclic radical may further optionally include spirodisubstitution and substitution of two adjacent or vicinal atoms forming a further 5- to 6-membered cyclic or heterocyclic, saturated, partially saturated, or aromatic ring. Examples of such heterocyclic radicals include 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, etc.

[0054] A dash ("-") without a dash between two letters or symbols is intended to represent a substituent bond. In diagrams, the bond of a cyclic functional group is shown by a dot ("·") localized to one of the available ring atoms to which the functional group can bond or to other fragments of the molecule.

[0055] The oxo portion is represented by (O) as an alternative to other common notations, such as (=O). Therefore, in terms of general formulas, the carbonyl group is represented here as -C(O)-, and generally, groups in parentheses are side-chain groups that are not included in the chain, and when it is considered useful to use parentheses, it helps to avoid ambiguity with linear chemical formulas; for example, the sulfonyl group -SO2- is also represented as -S(O)2- to avoid ambiguity with, for example, the sulfine group -S(O)O-.

[0056] When a basic amino or quaternary ammonium group is present in the compound of formula I, physiologically acceptable anions may be present, selected from chlorides, bromides, iodides, trifluoroacetates, formates, sulfates, phosphates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates, p-toluenesulfonates, pamoates, and naphthalenedisulfonates. Similarly, in the presence of acidic groups such as COOH groups, corresponding physiological cationic salts, for example containing alkali or alkaline earth metal ions, may also be present.

[0057] It is clear that when the compound of formula (I) contains one or more stereocenters, it can exist as an optical stereoisomer.

[0058] When a compound of the present invention has at least one stereocenter, it may thus exist as an enantiomer. When a compound of the present invention has two or more stereocenters, it may further exist as a diastereoisomer. All such single enantiomers, diastereoisomers, and mixtures thereof in any ratio are encompassed within the scope of the present invention. The absolute configuration (R) or (S) of the carbon supporting the stereocenter is assigned according to the Caen-Ingold-Prelogue nomenclature rules based on the properties of the group.

[0059] The present invention further considers the corresponding deuterated derivatives of the compound of formula (I).

[0060] All of the preferred groups or embodiments described above and below may be combined with each other and applied similarly to the compounds of formula I, with appropriate modifications.

[0061] As described above, the present invention relates to a series of compounds represented by the general formula (I) detailed below, which possess antagonist properties for the receptor P2X3.

[0062] Unlike similar compounds in prior art, the compound of formula (I) of the present invention can act as an antagonist P2X3 in a substantially effective manner, as will be recognized by those skilled in the art when searching for suitable and effective compounds useful in the treatment of respiratory diseases, particularly chronic cough.

[0063] As shown in the experimental section, the compounds of formula (I) have a half-percentage inhibitory concentration (pIC) on the receptor for each compound. 50 It has the activity shown in Table 2, which is expressed as efficacy as ).

[0064] As a further advantage, the compound of formula (I) has been found to efficiently and selectively inhibit the P2X3 receptor, and is useful for treating respiratory diseases while avoiding adverse events such as loss of taste response. In fact, as can be seen from Table 3, the compound of formula (I) inhibits the P2X3 receptor. 2 / 3 In comparison, it shows greater activity towards the receptor P2X3.

[0065] Therefore, in one embodiment, the present invention is a general formula (I) as a P2X3 antagonist. [ka] [In the formula, X is selected from S, SO2, SO, or O; Z is selected from the group consisting of heteroaryls and aryls, where each such heteroaryl and aryl may be substituted with one or more groups selected from (C1-C3)alkyl-, halo, and (C1-C6)haloalkyl-; R1 is H or (C1-C4) alkyl; R2 is a heteroaryl (C1-C4)alkyl-, where either such alkyl or heteroaryl may be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl, and halo; R stands for (C1-C6)alkyl-, (C1-C6)alkyl-CN, (C1-C6)haloalkyl, -NR A R B , (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, (C3-C8)heterocycloalkyl-, (C3-C8)heteroaryl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-, R A O-(C1-C6)alkyl-O-(C1-C6)alkyl-, R A NH-C(O)-(C1-C4)alkyl-, R A R B NC(O)-(C1-C4)alkyl-, R A Selected from the group consisting of OC(O)(C1-C6)alkyl-, Here, all of these heterocycloalkyl groups are either unsubstituted or OH, -C(O)R A , -C(O)OR A , substituted with one or more groups selected from (C1-C6)haloalkyl, -NH-C(O)R1 and oxo; All of these cycloalkyls are -C(O)OR A and are substituted with one or more groups selected from (C1-C6) haloalkyl-, Each of these heteroaryls may be substituted with one or more groups selected from (C1-C6)alkyl-, -OH, and (C3-C6)cycloalkyl-; R A and R B In each case, it is independently H or (C1-C6)alkyl-, (C1-C6)haloalkyl-, -OR1, -SO2R C and selected from the group consisting of (C3-C6) cycloalkyl groups, where such cycloalkyl groups may be substituted with one or more -C(O)OR1 groups or otherwise. R A and R B These may, together with the nitrogen atom to which they are bonded, form a five- or six-membered saturated heterocyclic monocyclic ring system containing a further heteroatom, which may optionally be nitrogen or oxygen, and which may optionally be substituted with one or more groups selected from halo, -OR1; R C is an arrow; However, R is (C1-C6) alkyl- or unsubstituted (C3-C8) heterocycloalkyl- only when X is S or SO. Regarding the compounds.

[0066] In a preferred embodiment, Z is selected from the group consisting of heteroaryls and aryls, where the heteroaryl is selected from pyridines and pyrimidines.

[0067] In a more preferred embodiment, R2 is a heteroaryl(C1-C4)alkyl-, where the heteroaryl is selected from the group consisting of pyridazine, thiadiazole, pyrimidine, and oxadiazole.

[0068] In a preferred embodiment, the present invention refers to at least one of the compounds listed in Table 1 below and a pharmaceutically acceptable salt thereof.

[0069] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0070] In one preferred embodiment, the present invention is expressed by formula (I) [ka] [In the formula, X is selected from S or SO; Z is an aryl group, where such an aryl group may be substituted with one or more groups selected from (C1-C3)alkyl-, halo-, and (C1-C6)haloalkyl-; R1 is H or (C1-C4) alkyl; R2 is a heteroaryl (C1-C4)alkyl-, where either such alkyl or heteroaryl may be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl, and halo; R is selected from the group consisting of (C1-C6) alkyl- and (C3-C8) heterocycloalkyl-. Regarding the compounds.

[0071] In one preferred embodiment, the present invention is represented by formula Ia [ka] [In the formula, Z is selected from the group consisting of heteroaryls and aryls, where each of such heteroaryls and aryls may be substituted with one or more groups selected from (C1-C3)alkyl-, halo, and (C1-C6)haloalkyl-; R1 is H or (C1-C4) alkyl; R2 is a heteroaryl (C1-C4)alkyl-, where either such alkyl or heteroaryl may be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl, and halo; R stands for (C1-C6)alkyl-, (C1-C6)alkyl-CN, (C1-C6)haloalkyl, -NR A R B , (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, (C3-C8)heterocycloalkyl-, (C3-C8)heteroaryl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-(C1-C6)alkyl-, (C3-C8)cycloalkyl-, R A O-(C1-C6)alkyl-O-(C1-C6)alkyl-, R A NH-C(O)-(C1-C4)alkyl-, R A R B NC(O)-(C1-C4)alkyl-, R A Selected from the group consisting of OC(O)(C1-C6)alkyl-, Here, any of such heterocycloalkyls is substituted with one or more groups selected from -OH, -C(O)R A , -C(O)OR A , (C1-C6) haloalkyl, -NH-C(O)R1, and oxo; any of such cycloalkyls is substituted with one or more groups selected from -C(O)OR A and (C1-C6) haloalkyl-; any of such heteroaryls may optionally be substituted with one or more groups selected from (C1-C6) alkyl-, -OH, and (C3-C6) cycloalkyl-; R A and R B are each independently H or selected from the group consisting of (C1-C6) alkyl-, (C1-C6) haloalkyl-, -OR1, -SO2R C and (C3-C6) cycloalkyl, where such cycloalkyl may optionally be substituted with one or more -C(O)OR1; R C is aryl. ]] Relates to a compound of formula (I) wherein X is O, represented by

[0072] In a certain preferred embodiment, the present invention relates to formula Ib

Chemical formula

[0073] Compounds of formula (I) containing all or at least one of the compounds listed above can generally be prepared by methods generally known and by the methods detailed in the scheme shown below.

[0074]

Chemical formula

[0075] ed. In certain embodiments of the invention, compound (Ia) can be prepared from compound (II) according to Scheme 1. Compound (II) was prepared by the method described in J. Med Chem., 2015, 58 (8), 3548-3571.

[0076] Compound (III) can be prepared from compound (II) by a deamination reaction mediated by a coupling agent such as PyBOP and a suitable amine (reagent 1).

[0077] Compound (VI) can be prepared from compound (III) by a Stille or Suzuki or similar metal-catalyzed cross-coupling reaction using a suitable reagent such as (reagent 2) or as described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004.

[0078] Alternatively, compound (V) can be prepared from compound (III) by a metal-catalyzed Miyaura borylation reaction.

[0079] Compound (VI) can be prepared from compound (V) by a similar metal-catalyzed cross-coupling reaction, such as that described by Still or Suzuki et al., or in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004, using a suitable organic halogen compound such as (reagent 3).

[0080] In other embodiments, compound (IV) was prepared by a metal-catalyzed cross-coupling reaction, such as Still, Suzuki, or similar methods described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004, starting from compound (II) and using a suitable organometallic reagent such as (reagent 2).

[0081] Compound (VI) can be prepared from compound (V) by a deoxyamination reaction mediated by a reagent such as PyBOP or a similar substance and a suitable amine (reagent 1).

[0082] Compound (VII) can be prepared from compound (VI) by means of a dealkylation reaction disclosed with a strong Lewis acid such as BBr3 or an equivalent.

[0083] Compound (Ia) was prepared from compound (VII) by alkylation with a suitable alkylating agent (reagent 4), such as alkyl chloride, bromide, iodide, mesylate, tosylate, or similar.

[0084] Alternatively, compound (Ia) can be prepared from compound (VII) and a suitable alcohol (reagent 5) by a Mitsunobu-like reaction mediated, for example, by DEAD / PPh3, DIAD / PPh3, or CMT.

[0085] Some compounds (Ia) may contain protected hydroxyl or amino groups, which are subsequently removed by known methods.

[0086] [ka]

[0087] In one embodiment of the present invention, compound (Ia) can be prepared from compound (VIII) according to scheme 2.

[0088] Compound (IX) can be prepared from compound (VIII) and a suitable alcohol (reagent 4) by aromatic substitution in the presence of a suitable base, such as potassium carbonate (K2CO3).

[0089] Compound (X) can be prepared from compound (IX) by hydrogenation, for example, in the presence of a suitable catalyst such as palladium-carbon.

[0090] Compound (XI) can be prepared from compound (X) by halogenation with a suitable reagent such as bromine, NBS, NIS, iodine, iodonium salt, or similar.

[0091] Compound (XII) can be prepared from compound (XI) by a metal-catalyzed cross-coupling reaction such as the Still, Suzuki, or similar reaction using a suitable organometallic reagent (reagent 2), such as an organoboron compound.

[0092] Compound (XIII) can be prepared from compound (XII) by ester hydrolysis mediated by a suitable base, such as lithium hydroxide (LiOH).

[0093] Compound (XIV) can be prepared from compound (XIII) by a quinazoline ring construction reaction using a suitable reagent such as formamide or an analogue.

[0094] Compound (XV) can be prepared from compound (XIV) by a deoxyhalogenation reaction mediated by a reagent such as phosphorus oxychloride.

[0095] Compound (Ia) can be prepared from compound (XV) by reaction with a suitable amine (reagent 1) in the presence of a base such as TEA or DIPEA.

[0096] Some compounds (Ia) may contain protected hydroxyl or amino groups, which are subsequently removed by known methods.

[0097] [ka]

[0098] In another embodiment of the present invention, compound (Ia) may also be prepared from compound (XI) according to scheme 2a.

[0099] Compound (XIIa) can be prepared from compound (XI) by ester hydrolysis mediated by a suitable base, such as lithium hydroxide (LiOH).

[0100] Compound (XIIIa) can be prepared from compound (XIIa) by a quinazoline ring construction reaction using a suitable reagent such as formamide or an analogue.

[0101] Compound (XIV) can be prepared from compound (XIIIa) by a metal-catalyzed cross-coupling reaction such as the Still, Suzuki, or similar reaction using a suitable organometallic reagent (reagent 2), such as an organoboron compound.

[0102] Compound (Ia) can be prepared from compound (XIV) as already described in Scheme 2.

[0103] [ka]

[0104] In another embodiment of the present invention, compound (Ib) may be prepared from compound (XVI) according to scheme 3.

[0105] Compound (XVII) can be prepared from compound (XVI) by an amination reaction in the presence of a suitable amine (reagent 6).

[0106] Compound (XVIII) can be prepared from compound (XVII) by halogenation with a suitable reagent such as bromine, NBS, NIS, iodine, iodonium salt, or similar.

[0107] Compound (XIX) can be prepared from compound (XVII) by a quinazoline ring construction reaction using a suitable reagent such as formamide or an analogue.

[0108] Compound (XX) can be prepared from compound (XIX) by a metal-catalyzed cross-coupling reaction such as the Still, Suzuki, or similar reaction using a suitable organometallic reagent (reagent 2), such as an organoboron compound.

[0109] Compound (Ib) can be prepared from compound (XX) by an amination reaction in the presence of a suitable amine (reagent 1).

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

[0111] [ka]

[0112] In another embodiment of the present invention, compounds (Ic) and (Id) can be prepared from compound (XXI) according to scheme 4.

[0113] Compound (XXII) can be prepared from compound (XXI) by metal-catalyzed thiolation with a suitable organosulfur agent (reagent 7).

[0114] Compound (Ic) can be prepared from compound (XXII) by a deoxyamination reaction mediated by a coupling agent such as PyBOP and a suitable amine (reagent 1).

[0115] Alternatively, compound (XXIII) can be prepared from compound (XXI) by a deoxyamination reaction mediated by a coupling agent such as PyBOP and a suitable amine (reagent 1).

[0116] Compound (Ic) can be prepared from compound (XXIII) by metal-catalyzed thiolation with a suitable organosulfur agent (reagent 7).

[0117] Compound (Id) can be prepared from compound (Ic) by an oxidation reaction with a reagent such as mCPBA.

[0118] Alternatively, compound (XIIa) can be prepared by oxidation reaction with a reagent such as mCPBA from compound (XII).

[0119] Compound (Id) can be prepared from compound (XXIIa) by a deoxyamination reaction mediated by a coupling agent such as PyBOP and a suitable amine (reagent 1).

[0120] Compound (Id) can be prepared from compound (XXIIa) by a deoxyamination reaction mediated by a coupling agent such as PyBOP and a suitable amine (reagent 1).

[0121] Some compounds (Ic) may contain protected hydroxyl or amino groups, which are subsequently removed by known methods.

[0122] The compounds of the present invention have been found to efficiently inhibit the P2X3 receptor, and are therefore useful in the treatment of respiratory diseases.

[0123] In one embodiment, the compound of the present invention represented by formula (I) was found to remarkably efficiently and selectively inhibit the P2X3 receptor, and the compound is useful for treating respiratory diseases while avoiding adverse events such as loss of taste response.

[0124] In a preferred embodiment, the compound of formula (I) is a selective P2X3 antagonist, where the selective P2X3 antagonist is P2X 2 / 3 It is at least 10 times more selective for P2X3 homomer receptor antagonism than for heteromer receptor antagonism.

[0125] In a more preferred embodiment, the selective P2X3 antagonist is P2X 2 / 3 It is at least 30 times more selective for P2X3 homomer receptor antagonism than for heteromer receptor antagonism.

[0126] In a more preferred embodiment, the selective P2X3 antagonist is P2X 2 / 3 It is at least 50-fold more selective for P2X3 homomer receptor antagonism than for heteromer receptor antagonism.

[0127] The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or additives, either alone or in combination with one or more further active ingredients.

[0128] In one embodiment, the present invention relates to a compound of formula (I) for use as a pharmaceutical.

[0129] In a further embodiment, the present invention relates to the use of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of disorders associated with the P2X3 receptor mechanism, preferably respiratory diseases.

[0130] Preferably, the present invention relates to compounds of formula (I) for use in the prevention and / or treatment of respiratory diseases, preferably cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, postviral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0131] More preferably, the present invention relates 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.

[0132] The present invention also provides a method for preventing and / or treating disorders associated with the P2X3 receptor mechanism, the method comprising administering a therapeutically effective amount of the compound of the present invention to a patient in need of such treatment.

[0133] The present invention relates in particular to methods for the prevention and / or treatment of cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, postviral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm, wherein the method comprises administering an appropriate amount of a compound of formula (I) to a patient in need thereof.

[0134] In a more preferred embodiment, the disorder is chronic cough.

[0135] The treatment method of the present invention involves administering a safe and effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need. As used herein with respect to the compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent, “safe and effective amount” means an amount of the compound sufficient to treat the patient’s condition but low enough to cause severe side effects, and nevertheless may be conventionally determined by those skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a single dose or in multiple doses at various intervals over a period of time according to a drug regimen. A typical daily dose may vary depending on the specific route of administration chosen.

[0136] The present invention also provides pharmaceutical compositions of the compound of formula (I) mixed with one or more pharmaceutically acceptable carriers or additives, for example, those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0137] The compounds of the present invention and their pharmaceutical compositions can be administered, for example, orally, nasally, non-enterally (subcutaneous, intravenously, intramuscularly, intrasternally, and intravenously) and by inhalation, depending on the patient's needs.

[0138] Preferably, the compounds of the present invention can be administered orally or by inhalation. More preferably, the compounds of the present invention are administered orally.

[0139] Various solid oral administration forms can be used for administering the compounds of the present invention, including solid forms such as tablets, gel caps, capsules, caplets, granules, lozenges, and active pharmaceutical ingredient powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known additives, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, and lubricants. Sustained-release capsules, tablets, and gels can also be used for administering the compounds of the present invention. advantageous That is the case.

[0140] Preferably, the compound of the present invention is administered in the form of a tablet.

[0141] Various liquid oral administration 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 administration forms may also include suitable known inert diluents such as water, and suitable known additives such as preservatives, humectants, sweeteners, flavorings, and agents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention may be administered, for example, intravenously in the form of an isotonic sterile solution.

[0142] For the treatment of respiratory tract diseases, the compounds of the present invention are preferably administered by inhalation.

[0143] Inhalable agents include inhalable powders, quantified aerosols containing propellants, or inhalable formulations without propellants.

[0144] For administration as a dry powder, single-dose or multi-dose inhalers known from prior literature may be used. In this case, the powder may be filled into a cap, plastic or other capsule, cartridge, blister pack, or reservoir.

[0145] A chemically inert diluent or carrier, such as lactose, or any other additive suitable for improving the inhalability fraction, may be added to the powder compound of the present invention.

[0146] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain the compounds of the present invention in solution or in dispersion form. The propellant-driven formulation may also contain other components such as cosolvents, stabilizers, and optionally other additives.

[0147] The propellant-free inhalable agent containing the compound of the present invention may be in the form of a solution or suspension in an aqueous, alcoholic, or hydroalcoholic medium and may be delivered by a jet or ultrasonic nebulizer or soft mist nebulizer as known in the prior art.

[0148] Preferably, the compound of the present invention is administered orally.

[0149] The compounds of the present invention can be administered as a sole active ingredient or in combination with other pharmaceutically active ingredients.

[0150] Preferably, the compounds of the present invention can be combined with therapeutic agents or active ingredients useful for treating diseases associated with or mediated by the P2X3 receptor.

[0151] The dosage of the compound of the present invention depends on a variety of factors, including, in particular, the specific disease being treated, the severity of the symptoms, and the route of administration.

[0152] The present invention also relates to a device comprising a pharmaceutical composition containing a compound of formula (I) of the present invention, in the form of a single-dose or multi-dose dry powder inhaler or a metered-dose inhaler.

[0153] Various aspects of the present invention described herein will be illustrated by the following examples, which are not intended to limit the invention in any way. The following examples illustrate the present invention. [Examples]

[0154] The test examples described herein are provided to illustrate the present invention and are not limited to examples illustrating the present invention.

[0155] Preparation of intermediates and example compounds Chemical names were generated using Dotmatics software. In some cases, commonly accepted names for commercially available reagents were used instead of the names generated by Dotmatics software.

[0156] All reagents whose synthesis is not described in the experimental section are commercially available, known compounds, or can be formed from known compounds by methods known to those skilled in the art.

[0157] (R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethanamine HCl and (R)-1-(6-methylpyridazin-3-yl)ethane-1-amine HCl were prepared by the method described in WO2016 / 091776.

[0158] Abbreviations - Meaning Et2O: Diethyl ether; Et3N: Triethylamine; TEA: Triethylamine; DCC: N,N'-Dicyclohexylcarbodiimide; PyBOP: (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; DMF: Dimethylformamide; æ: 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(diphenylphosphin)ferrocene; DIEA or DIPEA: N,N-diisopropylethylamine; MeCN: Acetonitrile; MTBE: tert-butyl methyl ether; TBDMSCl:tert-butyl(chloro)dimethylsilane; DMSO: Dimethyl sulfoxide; Boc2O: Ditert-butyl dicarbonate; UPLC: Ultra-high performance liquid chromatography. mCPBA: m-chloroperbenzoic acid

[0159] General experimental details and methods Analysis method Liquid chromatography - Mass spectrometry Method 1 UPLC-MS was performed on a Waters Acquity I-Class mass spectrometer 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). The initial phase was maintained with 5% acetonitrile / water (each mobile phase containing 0.1% formic acid) for 1.2 minutes, followed by a linear gradient of 5–100% for up to 3.5 minutes, and then maintained at 100% for 1.5 minutes (F = 0.5 mL / min).

[0160] Method 2 UPLC-MS was performed on a Waters Acquity I-Class equipped with a Waters diode array detector coupled to a Waters SQD2 single quadrupole mass spectrometer using a Waters BEH Shield RP18 column (1.7 μm, 100 × 2.1 mm). The phase was initially maintained at 5% acetonitrile / water (each mobile phase containing 10 mM ammonium bicarbonate) for 1.2 minutes, followed by a linear gradient of 5–100% for up to 3.5 minutes, and then maintained at 100% for 1.5 minutes (F = 0.5 mL / min).

[0161] Method 3 UPLC-MS was performed using a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer with an Acquity UPLC BEH Shield RP18 1.7μm 100×2.1mm (PlusGuard cartridge) maintained on a temp column. The cell was initially maintained in 5% acetonitrile / water (each mobile phase containing 10mM ammonium bicarbonate) for 0.4 minutes, followed by a linear gradient from 5% to 95% within 6.4 minutes, and then maintained at 95% for 1.2 minutes (F=0.4mL / min).

[0162] Method 4 UPLC-MS was performed on a Waters DAD + Waters SQD2, a single quadrupole UPLC-MS spectrometer, using an Acquity UPLC BEH Shield RP18 1.7 μm 100×2.1 mm (plus guard cartridge) maintained on a temp column. It was first maintained in 5% acetonitrile (Far UV grade) containing 0.1% (V / V) formic acid / water (high purity via PureLab Option unit) with 0.1% formic acid for 0.4 minutes, then linearly gradiented from 5 to 95% within 6.4 minutes, and then maintained at 95% for 1.2 minutes (F = 0.4 mL / min).

[0163] Method 5 An Acquity UPLC - QDa mass spectrometer equipped with a C18 reversed-phase column (Acquity CSH 50×2.1 mm with a particle size of 1.7 μm) maintained at 40 °C was eluted with A: 95 / 5 water / acetonitrile + 0.05% formic acid; B: 95 / 5 acetonitrile / water + 0.05% formic acid. Gradient:

Table12

[0164] Method 5A An Acquity UPLC - QDa mass spectrometer equipped with a C18 reversed-phase column (Acquity CSH 50×2.1 mm with a particle size of 1.7 μm) maintained at 40 °C was eluted with A: 95 / 5 water / acetonitrile + 0.05% formic acid; B: 95 / 5 acetonitrile / water + 0.05% formic acid. Gradient:

Table13

[0165] Method 6 Aquity UPLC-QDa mass spectrometer equipped with a C18 reversed-phase column (50 × 2.1 mm Acquity BEH with 1.7 μm particle size) maintained at 40°C was eluted with A: 95 / 5 water / acetonitrile + 0.05% concentrated ammonia; B: 95 / 5 acetonitrile / water + 0.05% concentrated ammonia. gradient: [Table 14] Detection - MS, UV PDA MS ionization method - electrospray (cations / anions)

[0166] Method 7 Kinetex maintained at 25°C (登録商標) A Dionex UHPLC Ultimate 3000 equipped with a 2.6 μm XB-C18 (4.6 × 50 mm) DAD detector / Thermo Scientific MSQ Pluse was used to analyze two solutions: A: 0.1% v / v aqueous solution of formic acid, and B: 0.1% v / v acetonitrile solution of formic acid. gradient: [Table 15] Detection - MS, UV PDA MS ionization method - electrospray (cations / anions)

[0167] NMR 1¹H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker or Varian instrument operating at 300 MHz or 400 MHz with the solvents described, near room temperature, unless otherwise specified. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are shown in parts per million using the conventional abbreviations for designating the main peak: e.g., s, singlet; d, doublet; t, triplet; q, quadruplet; dd, double doublet; dt, double triplet; m, multiplet; br, broad.

[0168] Preparative reverse-phase HPLC conditions Preparative HPLC purification was performed by reverse-phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV-directed system. The Waters 2767 liquid handler acted as both an autosampler and a fraction collector. The columns used for preparative purification of the compounds were Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl, 10 μm 19 × 150 mm, or Waters CSH Phenyl Hexyl, 19 × 150 mm, 5 μm columns. Appropriate intensification gradients were selected based on acetonitrile and methanol solvent systems under acidic or basic conditions. The modifiers used under acidic / basic conditions were formic acid or trifluoroacetic acid (0.1% V / V) and ammonium bicarbonate (10 mM), respectively. Purification was triggered using Waters Fractionlynx software with monitoring from 210 to 400 nm and a threshold collection value of 260 nm. When using Fractionlynx, the presence of target molecular ions was controlled by the presence of target molecular ions observed under API conditions. The collected fractions were analyzed by LC-MS (Waters Acquity system and Waters SQD).

[0169] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol The diastereomeric separation of the compound was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler equipped with Stacked Injection Module). The Waters 2767 liquid handler acted as both an autosampler and a fraction collector. Under unmodified or basic conditions, an appropriate isocratic method was selected based on a methanol, ethanol, or isopropanol solvent system. The standard SFC method used was modifier, CO2, 100 mL / min, 120 bar backpressure, and a column temperature of 40 °C. The modifier used under basic conditions was diethylamine (0.1% V / V). The modifiers used under acidic conditions were formic acid (0.1% V / V) or trifluoroacetic acid (0.1% V / V). SFC purification was controlled by monitoring from 210 to 400 nm with Waters Fractionlynx software and triggering at a typical threshold collection value of 260 nm. The collected fractions were analyzed by SFC (Waters / Thar SFC system equipped with Waters SQD). The fractions containing the desired product were concentrated by vacuum centrifugation.

[0170] Supercritical fluid chromatography-mass spectrometry analysis conditions Method 8 SFC-MS was performed on a Waters / Thar SFC system equipped with Waters SQD using a Lux Cellulose-3 column in a 15% methyl alcohol / CO2 (containing 0.1% diethylamine) isocratic run at 5 mL / min, 120 bar backpressure, and a column temperature of 40 °C.

[0171] Method 9 SFC-MS was performed on a Waters / Thar SFC system equipped with Waters SQD using a Lux Cellulose-3 column in a 20% methyl alcohol / CO2 (containing 0.1% diethylamine) isocratic run at 5 mL / min, 120 bar backpressure, and a column temperature of 40 °C.

[0172] Method 10 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed-composition run of 5 mL / min, 120 bar back pressure, and 40°C column temperature with 55% ethyl alcohol / CO2 (containing 0.1% diethylamine).

[0173] Method 11 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 20% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0174] Method 12 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 30% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0175] Method 13 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 50% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0176] Method 14 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed-composition run of 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0177] Method 15 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 15% ethyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0178] Method 16 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed composition run of 25% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0179] Method 17 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 35% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0180] Method 18 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed composition run of 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0181] Method 19 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 15% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0182] method 20 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 20% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0183] Method 21 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-C column, in a fixed-composition run of 15% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0184] Method 22 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-C column, in a fixed-composition run of 15% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0185] Method 23 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-C column, in a fixed-composition run of 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0186] Method 24 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, in a fixed composition run of 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0187] Method 25 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-3 column, in a fixed-composition run of 10% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0188] Method 26 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-3 column, in a fixed-composition run of 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0189] Method 27 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-3 column, in a fixed composition run of 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0190] Method 28 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 40% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0191] Method 29 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed-composition run of 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0192] method 30 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed-composition run of 5 mL / min, 120 bar back pressure, and 40°C column temperature with 50% methyl alcohol / CO2 (containing 0.1% diethylamine).

[0193] Method 31 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 5 mL / min, 120 bar back pressure, and 40°C column temperature with 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine).

[0194] Method 32 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a Lux Cellulose-4 column, in a fixed composition run of 5 mL / min, 120 bar back pressure, and 40°C column temperature with 55% methyl alcohol / CO2 (containing 0.1% diethylamine).

[0195] Method 33 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 20% ethyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0196] Method 34 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed composition run of 30% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0197] Method 35 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0198] method 36 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0199] Method 37 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, in a fixed-composition run of 5 mL / min, 120 bar back pressure, and 40°C column temperature with 55% methyl alcohol / CO2 (containing 0.1% diethylamine).

[0200] Method 38 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-C column, in a fixed-composition run of 20% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0201] Method 39 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, in a fixed composition run of 35% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0202] method 40 SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, in a fixed composition run of 45% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and 40°C column temperature.

[0203] Intermediate 1 2-amino-5-bromo-3-methoxybenzoate hydrobromide [ka] A 15 mL solution of bromine (6.0 g, 1.9 mL, 37.70 mmol) in chloroform was added dropwise to a 180 mL suspension of 2-amino-3-methoxybenzoic acid (6.0 g, 35.90 mmol) in chloroform at 0°C for 1 hour. The reaction mixture was stirred for a further 5 hours and slowly warmed to room temperature. The solvent was removed under reduced pressure, and the residue was ground with diethyl ether. The reaction mixture was filtered to obtain the title compound as a beige solid (11.3 g, 96%). LCMS (Method 4): [MH + ] = 247, 4.07 minutes

[0204] Intermediate 2 6-Bromo-8-methoxyquinazoline-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 hours. After returning to room temperature, the reaction mixture was diluted with water (100 mL), added to ice water (400 mL), and filtered. The solid was washed with water (200 mL) and diethyl ether (200 mL) to obtain the title compound as a light brown solid (5.9 g, 76%). LCMS (Method 4): [MH + ] = 255, 3.07 minutes

[0205] Intermediate 3 6-(4-fluorophenyl)-8-methoxyquinazoline-4-ol [ka] Nitrogen was bubbling for 5 minutes through a mixture of 6-bromo-8-methoxyquinazolin-4-ol (intermediate 2) (1.18 g, 4.63 mmol), 4-fluorophenylboronic acid (710 mg, 5.09 mmol), and cesium carbonate (5.73 g, 17.58 mmol) in 1,4-dioxane (30 mL) and water (7.5 mL). Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (190 mg, 0.23 mmol) was added, and the reaction mixture was heated at 110 °C for 5 hours. After returning to room temperature, the reaction mixture was diluted with water (20 mL), filtered, and the solid was washed with a 10% methanol diethyl ether solution, and then with diethyl ether to obtain the title compound (1.0 g, 80%) as a beige solid. LCMS (Method 5): [MH + ] = 271.1, 0.81 minutes

[0206] Intermediate 4 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazole-5-yl)ethyl)quinazoline-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), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (212 mg, 0.41 mmol) and di-isopropylethylamine (0.32 mL, 1.85 mmol) were successively added. The resulting mixture was heated to 40°C and stirred for 20 minutes, then 1-(3-methyl-1,2,4-oxadiazole-5-yl)ethane-1-amine (67 mg, 0.41 mmol) was added, and heating was maintained at 40°C for 18 hours. 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 hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (43 mg, 31%) as a white solid. 1 H NMR (400 MHz, DMSO): δ 8.85 (d, J = 6.8 Hz, 1 H), 8.49 (s, 1 H), 8.24 (s, 1 H), 7.99 (dd, J = 5.6, 8.6 Hz, 2 H), 7.61 (s, 1 H), 7.44 (dd, J = LCMS (Method 4): [MH + ] = 375, 3.29 minutes

[0207] The compounds listed in the table below were synthesized according to the same method described for the preparation of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazole-5-yl)ethyl)quinazoline-4-amine (intermediate 4). [Table 16]

[0208] Intermediate 6 (R)-6-bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazoline-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), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (139 mg, 0.27 mmol) and di-isopropylethylamine (0.2 mL, 0.81 mmol) were successively added. The resulting mixture was heated at 60°C for 1 hour, then (R)-1-(6-methylpyridazine-3-yl)ethane-1-amine (65 mg, 0.27 mmol) was added, and heating was maintained at 60°C for 18 hours. After returning to room temperature, the reaction mixture was concentrated directly on silica gel, purified by silica gel chromatography, and eluted with 0-100% (ethyl acetate solution in 10% MeOH) ethyl acetate solution to obtain the title compound as a beige solid (100 mg, quantitative yield). LCMS (Method 4): [MH + ] = 374, 2.42 minutes

[0209] The following intermediates listed in the table below were synthesized according to the same method described for the preparation of (R)-6-bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazoline-4-amine (intermediate 6): [Table 17]

[0210] Intermediate 9 6-(4-fluoro-2-methoxyphenyl)-8-methoxy-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine [ka] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (intermediate 8) (70 mg, 0.19 mmol) in 1,2-dimethoxyethane (3.0 mL), (4-fluoro-2-methoxyphenyl)boronic acid (41 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (8.2 mg, 0.01 mmol), cesium carbonate (130 mg, 0.40 mmol), and water (0.3 mL) were added. The resulting mixture was heated at 95°C for 18 hours. After returning to room temperature, the reaction product was filtered through Celite®. The Celite® cake was rinsed with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), filtered through hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound as a grayish-white solid (35 mg, 45%). 1 H NMR (400 MHz, DMSO): δ 8.92 (dd, J = 5.8, 5.8 Hz, 1 H), 8.41 (s, 1 H), 7.91 (d, J = 1.5 Hz, 1 H), 7.54-7.46 (m, 3 H), 7.37 (d, J = 1.4 Hz, 1 LCMS (Method 3): [MH + ] = 406, 3.97 minutes

[0211] The following compounds listed in the table below were prepared by adapting the above method, starting from the appropriate intermediates described in the table. [Table 18]

[0212] Intermediate 12 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-8-methoxy-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine [ka] Nitrogen was bubbling for 5 minutes through a mixture of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (intermediate 8) (100 mg, 0.28 mmol), bis(neopentyl glycolate)diborone (66 mg, 0.29 mmol), a [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (10 mg, 0.02 mmol), and potassium acetate (54 mg, 0.55 mmol) in 1,4-dioxane (3.0 mL). The mixture was heated at 100 °C for 3 hours. After returning to room temperature, the mixture was used in the next step as a 1,4-dioxane solution without further purification.

[0213] Intermediate 13 Preparation of 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazole-2-yl)quinazoline-4-amine [ka] To the above solution of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (100 mg, 0.28 mmol), 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) were added. The resulting mixture was heated at 95°C for 16 hours. After returning to room temperature, the mixture was filtered through Celite®, and the filter cake was rinsed with ethyl acetate (2 × 10 mL). The organic phase was washed with saturated aqueous ammonium chloride solution (10 mL), passed through hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound as a grayish-white solid (25 mg, 24%). 1 H NMR (400 MHz, DMSO): δ 9.24 (dd, J = 5.7, 5.7 Hz, 1 H), 8.43 (s, 1 H), 8.37 (d, J = 1.5 Hz, 1 H), 7.75 (d, J = 1.5 Hz, 1 H), 7.68 (d, J = 1.1 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 5.02 (d, J = 5.8 Hz, 2 H), 4.00 (s, 3 H), 2.60 (s, 3 H), 2.50 (s, 3 H). LCMS (Method 3): [MH + ] = 379, 3.20 minutes

[0214] The following compounds listed in the table below were prepared by the same method described for the preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazole-2-yl)quinazoline-4-amine (intermediate 13). [Table 19]

[0215] Intermediate 15 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-4-amine [ka] Nitrogen was bubbling for 5 minutes through a mixture of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (intermediate 8) (250 mg, 0.69 mmol), bis-(pinacolato)diborone (194 mg, 0.76 mmol), [1,1'-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II) (25 mg, 0.03 mmol), and potassium acetate (204 mg, 2.08 mmol) in 1,4-dioxane (15.0 mL). The mixture was heated at 90°C for 18 hours. After returning to room temperature, the reaction product was filtered through Celite® and the solvent was removed under reduced pressure. The residue was used in the next step without further purification.

[0216] Intermediate 16 8-Methoxy-6-(5-methyl-1,3,4-thiadiazole-2-yl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine [ka] Nitrogen was bubbling for 5 minutes 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)quinazoline-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), and then tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.02 mmol) was added. The resulting mixture was heated at 95°C for 16 hours. After returning to room temperature, the reaction product was filtered through Celite® and rinsed with ethyl acetate (20 mL). The organic phases were combined and the solvent was removed under reduced pressure by passing through hydrophobic frit. The residue was purified by preparative HPLC to obtain the title compound as a grayish-white solid (21.0 mg, 32%). 1 H NMR (400 MHz, DMSO): δ 9.31 (dd, J = 5.8, 5.8 Hz, 1 H), 8.47 (s, 1 H), 8.44 (d, J = 1.7 Hz, 1 H), 7.80 (d, J = 1.4 Hz, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 5.03 (d, J = 5.8 Hz, 2 H), 4.03 (s, 3 H), 2.84 (s, 3 H), 2.60 (s, 3 H). LCMS (Method 3): [MH + ] = 380, 2.13 minutes

[0217] The following compounds listed in the table below were prepared by the same method described for the preparation of 8-methoxy-6-(5-methyl-1,3,4-thiadiazole-2-yl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine (intermediate 16): [Table 20]

[0218] Intermediate 18 (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)-quinazoline-8-ol [ka] 6-(4-fluorophenyl)-8-methoxy-N-[(1R)-1-[2-(trifluoromethyl)-pyrimidine-5-yl]ethyl]quinazoline-4-amine (intermediate 10) (490 mg, 1.11 mmol) (intermediate 10) (8 mL) was dissolved in chloroform (0.32 mL, 3.32 mmol) dropwise at 0°C. The reaction mixture was then warmed to room temperature and heated at 65°C for 18 hours. After returning to room temperature, the reaction mixture was cooled in an ice bath and quenched with methanol (2 mL). The solvent was removed under reduced pressure. 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 hydrophobic frit, and the solvent was removed under reduced pressure to obtain the title compound as a gray solid (416 mg, 88%). 1 H NMR (400 MHz, DMSO): δ 9.18 (s, 2 H), 8.65 (d, J = 7.0 Hz, 1 H), 8.46 (s, 1 H), 8.09 (s, 1 H), 7.86 (dd, J = 5.5, 8.7 Hz, 2 H), 7.45 (d, J = 1.3 Hz, 1 H), 7.37 (dd, J = 8.8, 8.8 Hz, 2 H), 5.71-5.67 (m, 1 H), 1.75 (d, J = 7.0 Hz, 3 H), OH not observed

[0219] The following compounds were prepared by adapting the above method, starting from the substrates listed in the table. [Table 21]

[0220] [Table 22]

[0221] The following compounds listed in the table below were obtained as single isomers by chiral preparative SFC purification of the corresponding racemic mixtures, and were prepared by the same method as described for the preparation of 8-(2,2-difluoroethoxy)-6-(5-fluoropyridine-2-yl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine: [Table 23]

[0222] Example 8 8-(2,2-difluoroethoxy)-N-((6-methylpyridazine-3-yl)methyl)-6-(5-methylpyridine-2-yl)quinazoline-4-amine [ka]

[0223] Intermediate 28 2-amino-5-bromo-3-(2,2-difluoroethoxy)benzoic acid [ka] Methyl 2-amino-5-bromo-3-(2,2-difluoroethoxy)benzoate (1354 mg, 4.37 mmol) was dissolved in THF (30 mL) and methanol (30 mL). A solution of lithium hydroxide (157 mg, 6.55 mmol) in water (4 mL) was added, and the reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1351 mg, >100%) as an orange solid. 1 H NMR (400 MHz, MeOD): δ 7.56 (d, J = 2.3 Hz, 1 H), 6.89 (d, J = 2.3 Hz, 1 H), 6.25 (t, J = 3.9 Hz, 1 H), 6.12 (t, J = 3.8 Hz, 1 H), 5.98 (t, J = 3.8Hz, 1H), 4.17-4.08 (m, 2H)

[0224] Intermediate 29 6-Bromo-8-(2,2-difluoroethoxy)quinazolin-4-ol [ka] 2-amino-5-bromo-3-(2,2-difluoroethoxy)benzoic acid (1250 mg, 4.22 mmol) was dissolved in formamide (12 mL). The reaction mixture was stirred at 130°C for 24 hours. The mixture was diluted with water and filtered. The solid was then washed with water, followed by 9:1 diethyl ether / methanol to obtain the title compound (781 mg, 61%) as a light brown solid. 1 H NMR (400 MHz, DMSO): δ 8.12-8.11 (m, 1 H), 7.82 (d, J = 2.0 Hz, 1 H), 7.63-7.62 (m, 1 H), 6.61-6.31 (m, 1 H), 4.56-4.46 (m, 2 H)

[0225] Intermediate 29a 6-Bromo-4-chloro-8-(2,2-difluoroethoxy)quinazoline [ka] 6-Bromo-8-(2,2-difluoroethoxy)quinazolin-4-ol (400 mg, 1.31 mmol) was dissolved in toluene (14 mL), and DIPEA (1.1 mL, 6.56 mmol) was added. The mixture was heated at 90°C for 5 minutes. Phosphorus(V) oxychloride (0.15 mL, 1.57 mmol) was added, and the reaction mixture was heated at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned into DCM and sodium bicarbonate. The two phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phase was concentrated under reduced pressure to obtain the title compound (502 mg, >100%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 9.10-9.09 (m, 1 H), 8.12-8.10 (m, 1 H), 7.45 (d, J = 1.8 Hz, 1 H), 6.47-6.16 (m, 1 H), 4.53-4.45 (m, 2 H)

[0226] Intermediate 30 6-Bromo-8-(2,2-difluoroethoxy)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine [ka] 6-Bromo-4-chloro-8-(2,2-difluoroethoxy)quinazoline (424 mg, 1.31 mmol) was dissolved in dioxane (6 mL). DIPEA (1.1 mL, 6.55 mmol) and (6-methylpyridazin-3-yl)methanamine (308 mg, 1.57 mmol) were added, and the reaction mixture was heated at 95°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned into DCM and water. The two phases were separated. The aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography and eluted with ethyl acetate solution in 75% methanol to obtain the title compound (374 mg, 70%) as a light brown solid. 1 H NMR (400 MHz, DMSO): δ 9.05-9.00 (m, 1 H), 8.45-8.44 (m, 1 H), 8.24-8.22 (m, 1 H), 7.55-7.46 (m, 3 H), 6.49-6.47 (m, 1 H), 4.98-4.95 (m, 2 H), 4.57-4.46 (m, 2 H), 2.58 (s, 3 H)

[0227] Example 8 8-(2,2-difluoroethoxy)-N-((6-methylpyridazine-3-yl)methyl)-6-(5-methylpyridine-2-yl)quinazoline-4-amine [ka] 6-Bromo-8-(2,2-difluoroethoxy)-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (180 mg, 0.590 mmol), complex with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (24 mg, 0.0295 mmol), bis(pinacolato)diborone (180 mg, 0.708 mmol), and potassium acetate (69 mg, 0.708 mmol) were dissolved in dioxane (5 mL) and heated at 100°C for 2 hours. Then, 6-bromo-8-(2,2-difluoroethoxy)-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine (50 mg, 0.122 mmol) was added, and the reaction mixture was heated at 100°C for a further 16 hours. The reaction mixture was cooled to room temperature and reduced by half. 2-Bromo-5-methylpyridine (107 mg, 0.620 mmol), cesium carbonate (384 mg, 1.18 mmol), a complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and dichloromethane (24 mg, 0.0295 mmol), and water (2 mL) were added. The reaction mixture was heated at 100°C for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was partitioned into DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phase was concentrated under reduced pressure. Purification by preparative HPLC yielded the title compound (5 mg, 4%) as a white solid. 1 H NMR (400 MHz, DMSO): δ 9.23 (t, J = 5.7 Hz, 1 H), 8.72-8.70 (m, 1 H), 8.62 (d, J = 2.0 Hz, 1 H), 8.51-8.50 (m, 1 H), 8.18-8.13 (m, 2 H), 7.88-7.84 (m, 1 H), 7.63-7.53 (m, 2 H), 6.72-6.42 (m, 1 H), 5.11-5.07 (m, 2 H), 4.69-4.60 (m, 2 H), 2.65-2.64 (m, 3 H), 2.44-2.43 (m, 3 H). LCMS (Method 3): [MH + ] = 423, 4.01 minutes

[0228] The following compounds listed in the table below were prepared by the same method described for the preparation of 8-(2,2-difluoroethoxy)-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridine-2-yl)quinazoline-4-amine (Example 8): [Table 24]

[0229] Intermediate 31 2-amino-3-(morpholinosulfonyl)benzoic acid [ka] To a 50 ml aqueous solution of morpholine (0.741 ml, 8.47 mmol), 3-(chlorosulfonyl)-2-nitrobenzoic acid (0.75 g, 2.82 mmol) was added over 10 minutes, and the mixture was stirred for 30 minutes. Then, 10% Pd / C (50% wet) (2.82 mmol) and aqueous hydrogen dichloride solution (0.103 g, 2.82 mmol) were added, and the reaction mixture was stirred overnight under a hydrogen atmosphere (balloon). The catalyst was removed by filtration, and the solvent was removed under reduced pressure. The crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH:{(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0~0:100 to obtain 2-amino-3-(morpholinosulfonyl)benzoic acid (0.80 g, 2.79 mmol, 99% yield) as a brown solid. LCMS (Method 5): 0.75 min, [M+H]+287.75

[0230] The following compounds listed in the table below were prepared according to the above method. [Table 25]

[0231] Intermediate 37 Preparation of 2-amino-5-bromo-3-(morpholinosulfonyl)benzoic acid [ka] 2-amino-3-(morpholinosulfonyl)benzoic acid (0.8 g, 2.79 mmol) (intermediate 29) was added to a solution of DMF and NBS (0.567 ml, 2.79 mmol), and the solution was stirred for 30 minutes. The solvent was then removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH:{(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0~0:100 to obtain 2-amino-5-bromo-3-(morpholinosulfonyl)benzoic acid (0.85 g, 2.328 mmol, 83% yield) as a grayish-white solid. LCMS (Method 5): 0.98 min, 366.56 [M+H]+

[0232] The following compounds listed in the table below were prepared according to the above method. [Table 26]

[0233] Intermediate 43 6-Bromo-8-(morpholinosulfonyl)quinazoline-4-ol [ka] To a solution of 2-amino-5-bromo-3-(morpholinosulfonyl)benzoic acid (600 mg, 1.643 mmol) (intermediate 35) in formamide (6 ml), ethanesulfonic acid (0.6 ml, 1.643 mmol) was added, and the mixture was heated at 120 °C for 48 hours. The reaction product was loaded onto a C18 cartridge by direct reverse chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH:{(ACN / H2O) 95:5 + HCCOH 0.1%} 100:0~0:100, and 6-bromo-8-(morpholinosulfonyl)quinazolin-4-ol (0.230 g, 0.615 mmol, 37.4% yield) was obtained as a brown solid. LCMS (Method 5): 0.72 min [M+H]+375.56

[0234] The following compounds listed in the table below were prepared according to the above method. [Table 27]

[0235] Intermediate 50 6-(4-fluorophenyl)-8-(morpholinosulfonyl)quinazolin-4-ol [ka] To a suspension of 6-bromo-8-(morpholinosulfonyl)quinazolin-4-ol (250 mg, 0.668 mmol) in dioxane (10 ml), water (3 ml), 4-fluorophenylboronic acid (187 mg, 1.336 mmol), K2CO3 (277 mg, 2.004 mmol), and PdCl2 (dppf) (56 mg, 0.07 mmol) were added, and the reaction mixture was stirred overnight. Next, the solvent was removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0 ~ 0:100 to obtain 6-(4-fluorophenyl)-8-(morpholinosulfonyl)quinazolin-4-ol (204 mg, 0.524 mmol, 78% yield) as a brown solid. LCMS (Method 5): 0.87 min, [M+H]+389.81

[0236] The following compounds listed in the table below were prepared according to the above method. [Table 28] [Table 29]

[0237] Example 10 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-(morpholinosulfonyl)quinazolin-4-ol (60 mg, 0.154 mmol) in dry DMF (4 ml), PyBOP (96 mg, 0.185 mmol) and DIPEA (0.059 ml, 0.339 mmol) were added, and the reaction mixture was stirred for 30 minutes. Next, ((R)-1-(6-methylpyridazin-3-yl)ethane-1-amine dihydrochloride (32.4 mg, 0.154 mmol) was added, and the reaction mixture was stirred for a further 30 minutes. Then, the solvent was removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH}:{(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0~0:100 to obtain (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine (10 mg, 0.020 mmol, 12.76% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 2 H), 9.01 (br d, J = 6.58 Hz, 1 H), 8.95 (s, 1 H), 8.56 (s, 1 H), 8.54 (s, 1 H), 7.92 (br dd, J = 8.22, 5.59 Hz, 2 H), 7.43 (br t, J = 8.66 Hz, 2 H), 5.71 (br quin, J = 6.80 Hz, 1 H), 4.33 (br t, J = 4.82 Hz, 2 H), 3.52 - 3.61 (m, 4 H), 3.39 - 3.50 (m, 2 H), 1.75 (br d, J = 7.02 Hz, 3 H) LCMS (Method 5): 1.58 min, 509.13 [M+H]+

[0238] The following compounds listed in the table below were prepared using appropriate intermediates in accordance with the above method. [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36]

[0239] Example 24 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(piperazine-1-ylsulfonyl)quinazoline-4-amine [ka] To a solution of benzyl 4-((6-(4-fluorophenyl)-4-hydroxyquinazoline-8-yl)sulfonyl)piperazine-1-carboxylate (100 mg, 0.191 mmol) (intermediate 55) in dry DMF (5 ml), PyBOP (129 mg, 0.249 mmol) and DIPEA (0.100 ml, 0.574 mmol) were added, and the reaction mixture was stirred for 30 minutes. Then, (R)-1-(6-methylpyridazin-3-yl)ethane-1-amine dihydrochloride (40.2 mg, 0.191 mmol) was added, and the reaction mixture was stirred for another 30 minutes. The solvent was removed, and the crude product was redissolved in dry DCM (5.00 ml). A solution of 1 M boron tribromide in DCM (1.914 ml, 1.914 mmol) was added, and the reaction mixture was stirred for 1 hour. EtOH (2 mL) was added, then volatile matter was removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0 ~ 0:100 to obtain (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(piperazin-1-ylsulfonyl)quinazoline-4-amine (7 mg, 0.014 mmol, 7.21% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (br d, J = 6.58 Hz, 1 H), 9.08 (d, J = 1.75 Hz, 1 H), 8.64 (br s, 2 H), 8.54 (d, J = 1.75 Hz, 1 H), 8.50 (s, 1 H), 7.88 - 7.98 (m, 3 H), 7.76 (d, J = 8.77 Hz, 1 H), 7.41 (t, J = 8.77 Hz, 2 H), 5.76 (quin, J = 6.96 Hz, 1 H), 3.46 - 3.58 (m, 4 H), 3.09 (br s, 4 H), 2.62 (s, 3 H), 1.71 (d, J = 7.02 Hz, 3 H) UPLC PRECLI-WI-0183 minuti rt 4.29 min 508.18 m / z

[0240] The following compounds listed in the table below were prepared according to the above method. [Table 37]

[0241] Intermediate 56 Methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate [ka] Nitrogen is converted to methyl 2-amino-5-bromobenzoate (2.00g, 8.69 mmol), 4-fluorophenylboronic acid, pinacol ester (2.90g, 12.04 mmol), Tripotassium phosphate The mixture of (3.69 g, 17.39 mmol) and water (3.5 mL) in N,N-dimethylformamide (10.5 mL) was bubbling for 5 minutes, and then the [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (710 mg, 0.87 mmol) was added. The resulting mixture was heated at 100 °C for 1.25 hours. After returning to room temperature, the reaction product was diluted with water (100 mL) and diethyl ether (100 mL), and the organic phase was separated. The aqueous phase was further extracted with diethyl ether (100 mL), and then with ethyl acetate (100 mL). The organic phases were combined, washed with water (100 mL), dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography and eluted with a cyclohexane solution of 5-35% ethyl acetate to obtain the title compound as a grayish-white solid (2.08 g, 97%). 1 H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 2.3 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.08 (dd, J = 8.7, 8.7 Hz, 2 H), 6.74 (d, J = 8.6 Hz, 1 H), 5.78 (s, 2 H), 3.90 (s, 3 H)

[0242] Intermediate 57 Methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylate [ka] To a solution of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate (2.08 g, 8.48 mmol) in dichloromethane (25 mL), bis(pyridine)iodonium tetrafluoroborate (4.73 g, 12.72 mmol) and TFA (2.1 mL, 27.42 mmol) were added. The resulting mixture was stirred at room temperature for 2 days. HPLC analysis showed a 70% conversion, and bis(pyridine)iodonium tetrafluoroborate (1.25 g, 3.36 mmol) was added, and stirring was maintained for a further 2.5 hours. The reaction product 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 × 25 mL). The organic phases were combined, washed with 100 mL of 8% sodium thiosulfate aqueous solution, filtered through hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography and eluted with a cyclohexane solution of 0-25% ethyl acetate to obtain the title compound as a grayish-white solid (2.71 g, 86%). 1 H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1 H), 8.04-8.00 (m, 1 H), 7.46-7.41 (m, 2 H), 7.09 (dd, J = 8.6, 8.6 Hz, 2 H), 6.48-6.37 (m, 2 H), 3.91 (s, 3H)

[0243] Intermediate 58 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid [ka] Lithium hydroxide monohydrate (1.75 g, 41.87 mmol) was added 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). The mixture was stirred at room temperature for 18 hours. The reaction products were diluted with water (100 mL) and diethyl ether (100 mL) and separated. The aqueous phase was acidified to pH=1 with 1N HCl (45 mL) and extracted with dichloromethane (3 × 50 mL). The organic phases were combined, filtered through hydrophobic frit, and the solvent was removed under reduced pressure to obtain the title compound as a grayish-white solid (2.39 g, 96%). 1 H NMR (400 MHz, DMSO): δ 13.17 (s, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 8.09 (d, J = 2.3 Hz, 1 H), 7.65 (dd, J = 5.4, 8.5 Hz, 2 H), 7.27 (dd, J = 8.8, 8.8Hz, 2H), 6.84 (s, 2H)

[0244] Intermediate 59 6-(4-fluorophenyl)-8-iodoquinazoline-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 hours. After returning to room temperature, the reaction mixture was diluted with water (20 mL), stirred for 20 minutes, and then filtered. The solid was washed with water (3 × 5 mL) and then with a 10% MeOH diethyl ether solution (3 × 5 mL) to obtain the title compound as a grayish-white solid (2.14 g, 87%). 1H NMR (400 MHz, DMSO): δ 12.57 (s, 1 H), 8.66 (s, 1 H), 8.36 (s, 1 H), 8.28 (s, 1 H), 7.89 (dd, J = 5.6, 7.8 Hz, 2 H), 7.38 (dd, J = 8.6, 8.6 Hz, 2H)

[0245] Intermediate 60 6-(4-fluorophenyl)-8-(methylthio)quinazolin-4-ol [ka] To a solution of 6-(4-fluorophenyl)-8-iodoquinazolin-4-ol (0.5 g, 1.366 mmol) in dried DMSO (5 ml), sodium methanethiolate (0.096 g, 1.366 mmol), copper(I) iodide (0.260 g, 1.366 mmol), and cyclohexane-1,2-diamine (0.156 g, 1.366 mmol) were added, and the reaction mixture was stirred overnight at 130°C. The crude product was loaded onto a C18 cartridge by direct reverse chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCCOH 0.1%} 100:0 ~ 0:100, and 6-(4-fluorophenyl)-8-(methylthio)quinazolin-4-ol (0.25 g, 0.873 mmol, 63.9% yield) was obtained as a brown solid. LCMS (Method 5): 0.96 min, 286.75 [M+H]+

[0246] Example 26 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(methylthio)quinazoline-4-amine CRDD456-64-1 [ka] To a solution of 6-(4-fluorophenyl)-8-(methylthio)quinazolin-4-ol (40 mg, 0.140 mmol) (intermediate 60) in dried DMF (4 ml), PyBOP (95 mg, 0.182 mmol) and DIPEA (0.073 ml, 0.419 mmol) were added, and the reaction mixture was stirred for 30 minutes. Then, (R)-1-(6-methylpyridazine-3-yl)ethane-1-amine dihydrochloride (29.4 mg, 0.140 mmol) was added, and the reaction mixture was stirred for another 30 minutes. Next, the solvent was removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0 ~ 0:100 to obtain (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(methylthio)quinazoline-4-amine (6 mg, 0.015 mmol, 10.59% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.77 (d, J = 7.56 Hz, 1 H), 8.45 (d, J = 1.64 Hz, 1 H), 8.40 (s, 1 H), 7.96 (t, J = 6.54 Hz, 2 H), 7.68 (d, J = 1.64 Hz, 1 H), 7.61 (d, J = 8.88 Hz, 1 H), 7.49 (d, J = 8.55 Hz, 1 H), 7.39 (t, J = 8.88 Hz, 2 H), 5.74 - 5.79 (m, 1 H), 2.58 (s, 3 H), 2.56 (s, 3 H), 1.71 (d, J = 7.23 Hz, 3 H) UPLC PRECLI-WI-0183 minuti rt 5.98 min 406.23 m / z

[0247] Intermediate 61 6-(4-fluorophenyl)-8-(methylsulfinyl)quinazoline-4-ol CRDD456-65-1 [ka] To a 5 ml solution of 6-(4-fluorophenyl)-8-(methylthio)quinazolin-4-ol (100 mg, 0.349 mmol) in dried DCM, mCPBA (60.3 mg, 0.349 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was then diluted with 20 mL of DCM and washed with 20 mL of saturated aqueous solution of Na₂SO₃ and 20 mL of saturated aqueous solution of NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCCOH 0.1%} 100:0 to 0:100 to obtain 6-(4-fluorophenyl)-8-(methylsulfinyl)quinazolin-4-ol (55 mg, 0.182 mmol, 52.1% yield). LCMS (Method 5): 1.16 min, 302.75 [M+H]+

[0248] Example 27 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazin-3-yl)ethyl)-8-(methylsulfinyl)quinazoline-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-(methylsulfinyl)quinazolin-4-ol (50 mg, 0.165 mmol) (intermediate 61) in dry DMF (4 ml), PyBOP (112 mg, 0.215 mmol) and DIPEA (0.087 ml, 0.496 mmol) were added, and the reaction mixture was stirred for 30 minutes. Then, (R)-1-(6-methylpyridazine-3-yl)ethane-1-amine dihydrochloride (38.2 mg, 0.182 mmol) was added, and the reaction mixture was stirred for another 30 minutes. Next, the solvent was removed, and the crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0 ~ 0:100 to obtain 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazin-3-yl)ethyl)-8-(methylsulfinyl)quinazoline-4-amine (5 mg, 0.012 mmol, 7.17% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.05 - 9.10 (m, 1 H), 8.93 (dd, J = 5.09, 2.06 Hz, 1 H), 8.45 (d, J = 5.22 Hz, 1 H), 8.34 (d, J = 1.92 Hz, 1 H), 7.95 (t, J = 6.73 Hz, 2 H), 7.65 (d, J = 8.80 Hz, 1 H), 7.50 (d, J = 8.52 Hz, 1 H), 7.44 (t, J = 8.80 Hz, 2 H), 5.75 - 5.81 (m, 1 H), 2.90 - 2.93 (m, 3H), 2.58 - 2.59 (m, 3H), 1.73 (d, J = 7.01, 3H) UPLC PRECLI-WI-0183 minuti rt 5.16 min 422.24 m / z

[0249] Intermediate 61a (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-iodoquinazoline-4-(3H)-one (1.14 g, 3.11 mmol) in N,N-dimethylformamide (10 mL), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.03 g, 1.25 mmol) and di-isopropylethylamine (2.7 mL, 15.57 mmol) were successively added. The resulting mixture was heated at 45°C for 1 hour, then (R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethane-1-amine hydrochloride (0.96 g, 4.2 mmol) was added, and heating was maintained at 45°C for 2 hours. 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 hydrophobic frit, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography and eluted with a 0-15% ethyl acetate dichloromethane solution to obtain the title compound as a grayish-white solid (1.27 g, 75%). 1 H NMR (400 MHz, DMSO): δ 9.18 (s, 2 H), 8.88 (d, J = 6.9 Hz, 1 H), 8.71 (d, J = 1.8 Hz, 1 H), 8.67 (d, J = 1.8 Hz, 1 H), 8.51 (s, 1 H), 7.95-7.90 (m, 2 H), 7.40 (dd, J = 8.9, 8.9 Hz, 2 H), 5.73-5.67 (m, 1 H), 1.75 (d, J = 7.2 Hz, 3 H)

[0250] The following compounds listed in the table below were prepared using appropriate amines in accordance with the above method. [Table 38]

[0251] Example 28 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(oxetane-3-ylthio)quinazoline-4-amine [ka] To a dry solution of (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazoline-4-amine (400 mg, 0.824 mmol) (intermediate 61b), oxetane-3-thiol (74.3 mg, 0.824 mmol), copper(I) iodide (7.85 mg, 0.041 mmol), cyclohexane-1,2-diamine (0.020 ml, 0.165 mmol), and potassium phosphate (525 mg, 2.473 mmol) were added, and the reaction mixture was stirred overnight at 130°C. The reaction products were directly loaded onto a C18 cartridge by reverse chromatography ((H2O / ACN)) 95:5 + 0.1% HCCOH ): {(ACN / H2O) 95:5 + 0.1% HCCOH} 100:0 ~ 0:100 to obtain (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(oxetane-3-ylthio)quinazoline-4-amine (100 mg, 0.223 mmol, 27.1% yield) as a brown solid. UPLC PRECLI-WI-0183 minuti rt 4.22 min 448.25 m / z 1H NMR (600 MHz, DMSO-d6) δ ppm 8.13 (dd, J = 2.14, 1.48 Hz, 1 H), 7.90 (s, 1 H), 7.78 (dd, J = 12.00, 8.71 Hz, 1 H), 7.70 - 7.75 (m, 2 H), 7.67 - 7.69 (m, 1 H), 7.49 (dd, J = 8.88, 2.96 Hz, 1 H), 7.30 - 7.34 (m, 2 H), 5.68 - 5.75 (m, 1 H), 5.35 - 5.41 (m, 1 H), 4.19 - 4.28 (m, 2 H), 3.50 - 3.66 (m, 2 H), 2.58 (s, 3H), 1.45 (dd, J = 6.74, 4.77Hz, 3H)

[0252] Example 29 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazine-3-yl)ethyl)-8-(oxetane-3-ylsulfinyl)quinazoline-4-amine [ka] (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(oxetane-3-ylthio)quinazoline-4-amine (100 mg, 0.223 mmol) (Example 28) was dissolved in 5 ml of dried DCM, to which mCPBA (38.6 mg, 0.223 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was then diluted with 20 mL of DCM and washed with 20 mL of saturated Na2SO3 solution and 20 mL of saturated NaHCO3 aqueous solution. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by C18 flash chromatography ((H2O / ACN)) 95:5 + 0.1% HCOOH : {(ACN / H2O) 95:5 + HCOOH 0.1%} 100:0 ~ 0:100 to obtain 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazin-3-yl)ethyl)-8-(oxetane-3-ylsulfinyl)quinazoline-4-amine (10 mg, 0.022 mmol, 9.65% yield) as a pale yellow solid. LCMS (Method 5): 0.65 min, 467.27 [M+H]+ 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.59 (br s, 1 H), 8.39 (d, J = 1.65 Hz, 1 H), 8.00 - 8.08 (m, 1 H), 7.75 - 7.89 (m, 3 H), 7.50 (br d, J = 8.52 Hz, 1 H), 7.36 (t, J = 8.25 Hz, 2 H), 5.71 - 5.78 (m, 1 H), 5.36 - 5.41 (m, 1 H), 4.18 - 4.22 (m, 2 H), 3.58 - 3.80 (m, 2 H), 2.62 (s, 3 H), 1.47 (dd, J = 6.74, 3.16 Hz, 3 H)

[0253] Intermediate 62 (R)-6-(4-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine [ka] Nitrogen was bubbling for 5 minutes through a mixture of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-ol (40 mg, 0.01 mmol) (intermediate 10), tetrahydro-4-pyrano-1 (10 mg, 0.102 mmol), and cyanomethyltributylphosphoran (1 M in toluene, 0.14 mL, 0.14 mmol) in toluene (3.0 mL) of toluene. The mixture was heated at 100 °C for 72 hours. After returning to room temperature, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (17 mg, 38%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO): δ 9.18 (s, 2 H), 8.64 (d, J = 7.0 Hz, 1 H), 8.44 (s, 1 H), 8.23 ​​(d, J = 1.6 Hz, 1 H), 7.94-7.89 (m, 2 H), 7.65 (d, J = 1.6 Hz, 1 H), 7.39 (dd, J = 8.8, 8.8 Hz, 2 H), 5.71-5.66 (m, 1 H) 5.02-4.94 (m, 1 H), 3.96-3.88 (m, 2 H), 3.51 (dd, J = 9.7, 9.7 Hz, 2 H), 2.07-2.00 (m, 2 H), 1.74 (d, J = 7.0 Hz, 5 H). LCMS (Method 3): [MH + ] = 514, 3.79 minutes

[0254] The following compounds listed in the table below were prepared by the same method described for the preparation of (R)-6-(4-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine: [Table 38] [Table 39] [Table 40]

[0255] Intermediate 63 (R)-8-((3-(benzyloxy)isoxazole-5-yl)methoxy)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine [ka] Nitrogen was bubbling for 5 minutes through a mixture of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-ol (95 mg, 0.221 mmol), (3-(benzyloxy)isoxazole-5-yl)methanol (75 mg, 0.265 mmol), and cyanomethyltributylphosphoran (64 mg, 0.265 mmol) in toluene (4.0 mL). The mixture was heated at 100 °C for 72 hours. After returning to room temperature, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (140 mg) as a grayish-white solid, which was used in the next step without further purification.

[0256] Example 38 (R)-5-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)isoxazole-3-ol [ka] A mixture of (R)-8-((3-(benzyloxy)isoxazole-5-yl)methoxy)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine (140 mg, 0.227 mmol) in acetic acid (1 mL) was mixed with 48% aqueous hydrogen bromide (2 mL). The mixture was heated at 100 °C for 2 hours. After returning to room temperature, the reaction product was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (3.2 mg, 2.7% in two steps) as a grayish-white solid. 1 1H NMR (400 MHz, DMSO): δ 9.18 (s, 2 H), 8.69 (d, J = 6.9 Hz, 1 H), 8.43 (s, 1 H), 8.28 (d, J = 1.4 Hz, 1 H), 7.97-7.92 (m, 2 H), 7.71 (d, J = 1.4 Hz, 1 H), 7.41 (dd, J = 8.9, 8.9 Hz, 2 H), 6.16 (s, 1 H), 5.72-5.66 (m, 1 H), 5.41 (s, 2 H), 1.74 (d, J = 7.2 Hz, 3 H). OH not observed. LCMS (Method 3): [MH] + ] = 527, 3.60 minutes

[0257] Intermediate 64 Tert-butyl(R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetate [ka] Tert-butyl 2-bromoacetate (0.057 ml, 0.384 mmol) was added to a mixture of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-ol (150 mg, 0.349 mmol) (intermediate 10) and potassium carbonate (155 mg, 1.122 mmol) in DMF (3 ml) while being stirred. The mixture was stirred at rt for 1 hour, then the reaction mixture was diluted with EtOAC and washed with brine (2 ×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (gradient elution of a 0-50% ethyl dichloromethane solution at 15 CV using a Biotage Isolera, 10 g KP-Sil cartridge) yielded tert-butyl(R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetate (149 mg, 0.274 mmol, 78% yield) as a white powder. LCMS (Method 5): 0.97 min, m / z 544.2 [M+H]+,

[0258] Intermediate 65 (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetic acid [ka] Tert-butyl(R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetate (149 mg, 0.274 mmol) was dissolved in TFA (2 mL). The mixture was stirred at rt for 16 hours, and then volatile matter was removed under reduced pressure. By grinding with diethyl ether, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetic acid (134 mg, 0.275 mmol, 100% yield) was obtained as a pale pink powder. LCMS (Method 5): 0.81 min, m / z 488.1 [M+H]+, 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (bs, 1 H), 9.16 (s, 2 H), 8.55 (s, 1 H), 8.29 (s, 1 H), 7.87 (dd, J = 8.66, 5.37 Hz, 2 H), 7.65 (br s, 1 H), 7.38 (t, J = 8.77 Hz, 2 H), 5.75 (quin, J = 6.63 Hz, 1 H), 5.07 (s, 2 H), 1.73 (d, J = 7.02 Hz, 3 H)

[0259] Example 40 (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)-N-(phenylsulfonyl)acetamide [ka] EDCI (67.8 mg, 0.354 mmol) was added to a solution of (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetic acid (115 mg, 0.236 mmol) (intermediate 65), DIPEA (205 μl, 1.180 mmol), benzenesulfonamide (55.6 mg, 0.354 mmol), and DMAP (43.2 mg, 0.354 mmol) in DMF (2 mL) while stirring. The mixture was stirred at rt for 16 hours. The reaction mixture was diluted with ethyl acetate, and then formic acid (100 μl, 2.65 mmol) was added. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (Biotage Isolera, 30g C18 cartridge, gradient elution of solution A at 0-60% B; A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) yielded (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)-N-(phenylsulfonyl)acetamide (97.3 mg, 0.155 mmol, 65.8% yield) as a grayish-white powder. LCMS (Method 5): 0.96 min, 627.2 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (s, 2 H), 8.97 (br s, 1 H), 8.44 (s, 1 H), 8.24 (s, 1 H), 8.10 (s, 1 H), 7.72 - 7.88 (m, 4 H), 7.30 - 7.55 (m, 6 H), 5.65 - 5.74 (m, 1 H), 4.85 - 4.99 (m, 2 H), 2.64 (br s, 1 H), 2.50 - 1.71 (d, J = 7.23 Hz, 3 H)

[0260] Intermediate 66 Ethyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylate [ka] Cesium carbonate (152 mg, 0.466 mmol) was added to a mixture in DMF (2 mL) of ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (0.053 ml, 0.256 mmol) and (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-ol (100 mg, 0.233 mmol) (intermediate 10) while stirring. The reaction mixture was stirred at 60°C for 4 hours, then diluted with AcOEt and washed with brine. The organic layer was dried over sodium sulfate, then filtered and concentrated under reduced pressure. Purification by chromatography (gradient elution of 0-10% ethyl acetate in dichloromethane solution at Biotage Isolera, 28g NH cartridge, 15CV) yielded ethyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylate (68.1 mg, 0.123 mmol, 52.6% yield). LCMS (Method 5): 0.96 min, 556.1 m / z [M+H]+

[0261] Example 41 (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] A 1 mL aqueous solution of lithium hydroxide (15.2 mg, 0.635 mmol) was added to a 3 mL THF solution of ethyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylate (68.1 mg, 0.123 mmol). The mixture was stirred at rt for 16 hours. Volatile substances were removed under reduced pressure. Purification by chromatography (Biotage Isolera, 30g C18 cartridge, 15CV, 0-45% B A, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH solution gradient elution) yielded (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (5.1 mg, 9.67 μmol, 7.89% yield) as a grayish-white powder. LCMS (Method 5): 0.80 min, 527.8 m / z [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.34 - 12.62 (bs, 1 H), 9.12 (s, 2 H), 8.57 (br d, J = 7.02 Hz, 1 H), 8.38 (s, 1 H), 8.13 - 8.18 (m, 1 H), 7.85 - 7.95 (m, 2 H), 7.48 (s, 1 H), 7.34 (t, J = 8.77 Hz, 2 H), 5.64 (quin, J = 6.85 Hz, 1 H), 4.30 (s, 2 H), 1.69 (d, J = 7.02 Hz, 3 H), 1.01 - 1.28 (m, 4H)

[0262] Example 42 Methyl 1-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylate [ka] Methyl 1-(2-chloroacetamide)cyclopropane-1-carboxylate (49.6 mg, 0.259 mmol) was added to a mixture of 6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-8-ol (85 mg, 0.235 mmol) (intermediate 11) and potassium carbonate (98 mg, 0.706 mmol) in DMF (3 ml) while being stirred. The mixture was stirred at 80°C for 16 hours, then the reaction mixture was diluted with THF and washed with saturated ammonium chloride aqueous solution, and then with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (Biotage Isolera, 28g NH cartridge, gradient elution of solution A with 0-30% B; A: dichloromethane, B: dichloromethane / MeOH 90:10) yielded methyl 1-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopropane-1-carboxylate (44.0 mg, 0.085 mmol, 36.2% yield) as a grayish-white powder. LCMS (Method 5): 0.60 min, m / z 517.2 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 - 9.12 (m, 2 H), 8.43 (s, 1 H), 8.23 ​​- 8.28 (m, 1 H), 7.88 (dd, J = 8.77, 5.48 Hz, 2 H), 7.59 - 7.67 (m, 1 H), 7.43 - 7.55 (m, 2 H), 7.35 (t, J = 8.88 Hz, 2 H), 5.00 (d, J = 5.48 Hz, 2 H), 4.79 (s, 2 H), 3.43 (s, 3 H), 2.56 (s, 3 H), 1.25 - 1.45 (m, 2 H), 0.98 - 1.11 (m, 2 H)

[0263] The following compounds were prepared by adapting the above method, starting from the substrates listed in the table. [Table 42]

[0264] Example 44 (R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylic acid [ka] 2N LiOH (0.2 ml, 0.400 mmol) was added to a THF (3 ml) solution of methyl(R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopropane-1-carboxylate (50.9 mg, 0.087 mmol) (Example 43) while stirring. The mixture was stirred for 16 hours at 80°C. Volatile substances were removed under reduced pressure, and then DMF (2 mL), followed by formic acid (20 μl, 0.530 mmol), was added to the residue. The resulting suspension was purified by chromatography (Biotage Isolera, 12g C18 Ultra cartridge, gradient elution of solution A at 0-35% B; A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) to obtain (R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopropane-1-carboxylic acid (9.9 mg, 0.017 mmol, 19.93% yield) as a white powder. LCMS (method 5): 0.77 min, m / z 570.8 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 - 12.82 (bs, 1 H), 9.13 (s, 2 H), 8.90 (s, 1 H), 8.67 (br d, J = 7.02 Hz, 1 H), 8.43 (s, 1 H), 8.26 (s, 1 H), 7.88 (dd, J = 8.77, 5.48 Hz, 2 H), 7.61 (s, 1 H), 7.35 (t, J = 8.77 Hz, 2 H), 5.66 (quin, J = 6.80 Hz, 1 H), 4.75 (s, 2 H), 1.70 (d, J = 7.23 Hz, 3 H), 1.23 - 1.40 (m, 2 H), 0.90 - 1.03 (m, 2 H)

[0265] Intermediate 67a 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxyacetic acid, sodium salt [ka] NaOH (10.5 mg, 0.26 mmol) was added 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). The mixture was stirred at rt for 3 days, then diluted with diethyl ether and filtered to obtain 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetate sodium salt (87 mg, 75% yield) as a white powder.

[0266] Intermediate 68 Ethyl(1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylate [ka] PyAOP (82 mg, 0.157 mmol) was added to a mixture of 2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetic acid (55 mg, 0.131 mmol) (intermediate 67a), ethyl (1R,2S)-2-aminocyclopentane-1-carboxylate (24.74 mg, 0.157 mmol), and DIPEA (0.069 mL, 0.393 mmol) in THF (3 mL). The mixture was stirred at rt for 1 hour. The reaction was diluted with AcOEt and then washed with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (gradient elution of 0-100% siRNA dichloromethane solution at 25 CV using a Biotage Isolera, 28 g NH cartridge) followed by RP chromatography (gradient elution of 0-35% B solution A at 25 CV using a Biotage Isolera, 12 g C18 Ultra cartridge; A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) yielded ethyl (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopentan-1-carboxylate (21.4 mg, 0.038 mmol, 29.2% yield) as a grayish-white powder. LCMS (Method 5): 0.72 min, 559.4 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (t, J = 5.81 Hz, 1 H), 8.48 (d, J = 8.55 Hz, 1 H), 8.41 (s, 1 H), 8.26 (d, J = 1.53 Hz, 1 H), 7.84 - 7.91 (m, 2 H), 7.72 (d, J = 1.53 Hz, 1 H), 7.49 - 7.53 (m, 1 H), 7.44 - 7.49 (m, 1 H), 7.34 (t, J = 8.88 Hz, 2 H), 5.01 (d, J = 5.70 Hz, 2 H), 4.70 - 4.79 (m, 2 H), 4.36 - 4.43 (m, 1 H), 3.60 - 3.77 (m, 2 H), 2.89 (q, J = 7.31 Hz, 1 H), 2.55 (s, 3 H), 1.71 - 1.90 (m, 4 H), 1.47 - 1.62 (m, 2 H), 0.92 (t, J = 7.13Hz, 3H)

[0267] Example 45 (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylic acid [ka] 2N NaOH (0.050 mL, 0.100 mmol) was added to a solution of ethyl (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopentan-1-carboxylate (17.0 mg, 0.030 mmol) (intermediate 68) in MeOH (2 mL) while stirring. After 64 hours, volatile matter was removed under reduced pressure. Purification by chromatography (Gradient elution of solution A with 0-25% B at Biotage Isolera, 12g C18 cartridge, 30CV; A: Water / Acetonitrile 95:5 + 0.1% HCOOH, B: Acetonitrile:Water 95:5 + 0.1% HCOOH) yielded (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopentan-1-carboxylic acid (11.5 mg, 0.022 mmol, 71.2% yield) as a grayish-white powder. LCMS (Method 5): 0.72 min, 559.4 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.06 - 9.15 (m, 1 H), 8.73 (d, J = 7.89 Hz, 1 H), 8.36 - 8.46 (m, 1 H), 8.22 - 8.29 (m, 1 H), 7.78 - 7.91 (m, 2 H), 7.64 - 7.72 (m, 1 H), 7.43 - 7.54 (m, 2 H), 7.29 - 7.38 (m, 2 H), 5.00 (d, J = 5.48 Hz, 2 H), 4.70 - 4.78 (m, 2 H), 4.27 (t, J = 7.13 Hz, 1 H), 3.45 - 3.65 (m, 1 H), 2.55 (s, 3 H), 1.35 - 1.97 (m, 6 H)

[0268] Example 46 Ethyl(1S,2R)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylate [ka] PyAOP (82 mg, 0.157 mmol) was added to a mixture of 2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetic acid (55 mg, 0.131 mmol) (intermediate 67a), ethyl (1S,2R)-2-aminocyclopentane-1-carboxylate (25 μL, 0.131 mmol), and DIPEA (68.5 μL, 0.393 mmol) in THF (3 mL). The mixture was stirred at rt for 1 hour. Formic acid (29.7 μL, 0.787 mmol) was then added, and volatile matter was removed under reduced pressure. Purification by chromatography (Biotage Isolera, 30g C18 cartridge, gradient elution of solution A with 0-30% B at 30CV; A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) yielded ethyl (1S,2R)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamido)cyclopentan-1-carboxylate (27.5 mg, 0.049 mmol, 37.5% yield) as a grayish-white powder. LCMS (Method 5): 0.72 min, 559.4 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (t, J = 5.81 Hz, 1 H), 8.48 (d, J = 8.55 Hz, 1 H), 8.41 (s, 1 H), 8.26 (d, J = 1.53 Hz, 1 H), 7.84 - 7.91 (m, 2 H), 7.72 (d, J = 1.53 Hz, 1 H), 7.49 - 7.53 (m, 1 H), 7.44 - 7.49 (m, 1 H), 7.34 (t, J = 8.88 Hz, 2 H), 5.01 (d, J = 5.70 Hz, 2 H), 4.70 - 4.79 (m, 2 H), 4.36 - 4.43 (m, 1 H), 3.60 - 3.77 (m, 2 H), 2.89 (q, J = 7.31 Hz, 1 H), 2.55 (s, 3 H), 1.71 - 1.90 (m, 4 H), 1.47 - 1.62 (m, 2 H), 0.92 (t, J = 7.13Hz, 3H)

[0269] Intermediate 69 1-(tert-butyl)4-ethyl(R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-1,4-dicarboxylate [ka] Cesium carbonate (152 mg, 0.466 mmol) was added to a mixture in DMF (2 mL) of 1-(tert-butyl)4-ethyl4-(iodomethyl)piperidine-1,4-dicarboxylate (102 mg, 0.256 mmol) and (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-ol (100 mg, 0.233 mmol) (intermediate 10) while stirring. The mixture was stirred for 5 hours at 100°C. The reaction mixture was diluted with AcOEt and washed with brine. The organic layer was dried over sodium sulfate, then filtered and concentrated under reduced pressure. Purification by chromatography yielded 1-(tert-butyl)4-ethyl(R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-1,4-dicarboxylate (39.9 mg, 0.057 mmol, 24.52% yield). LCMS (Method 5): 1.07 min, 698.8 m / z [M+H]+

[0270] Intermediate 70 (R)-1-(tert-butoxycarbonyl)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylic acid [ka] A solution of lithium hydroxide (140 mg, 5.85 mmol) in water (1 mL) was added to a solution of 1-(tert-butyl)4-ethyl(R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-1,4-dicarboxylate (39.9 mg, 0.057 mmol) in THF (3 mL). The mixture was stirred at rt for 16 hours. Formic acid (300 μl, 7.95 mmol) was added, and volatile matter was removed under reduced pressure. Purification by chromatography (Biotage Isolera, 30g C18 cartridge, 15CV, 0-55% B A, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH solution gradient elution) yielded (R)-1-(tert-butoxycarbonyl)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylic acid (17.9 mg, 0.027 mmol, 46.7% yield) as a grayish-white powder. LCMS (Method 5): 0.96 min, 670.8 m / z [M+H]+, 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.91 - 13.22 (bs, 1 H), 9.12 (s, 2 H), 8.56 (br d, J = 6.80 Hz, 1 H), 8.38 (s, 1 H), 8.17 (s, 1 H), 7.90 (dd, J = 8.66, 5.59 Hz, 2 H), 7.53 (s, 1 H), 7.34 (t, J = 8.88 Hz, 2 H), 5.63 (br t, J = 6.91 Hz, 1 H), 4.28 (s, 2 H), 3.66 (br d, J = 13.59 Hz, 2 H), 2.94 - 3.20 (m, 2 H), 2.01 (br d, J = 13.81 Hz, 2 H), 1.69 (d, J = 7.02 Hz, 3 H), 1.57 - 1.66 (m, 2 H), 1.36 (s, 9 H)

[0271] Example 47 (R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylate hydrochloride [ka] 37% HCl (0.5 mL, 6.00 mmol) was added to a mixture of (R)-1-(tert-butoxycarbonyl)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylic acid (12.3 mg, 0.018 mmol) (intermediate 65) in a 1 M HCl AcOEt solution (2 mL, 2.000 mmol). The mixture was stirred at rt for 48 hours. Volatile substances were removed under reduced pressure. Purification by RP chromatography (Biotage Isolera, 12g C18 cartridge, 15CV with 0-25% B A, A: water / acetonitrile 95:5 + 0.1% concentrated HCl, B: acetonitrile:water 95:5 + 0.1% concentrated HCl solution gradient elution) yielded (R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylate hydrochloride (6.1 mg, 10.05 μmol, 54.8% yield). LCMS (Method 5): 0.59 min, 570.8 m / z [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 13.9 (br s, 0.5 H), 13.1 (br s, 1 H), 10.7 (br s, 0.5 H), 9.19 (br s, 2 H), 9.05 - 8.30 (m, 4 H), 8.10 - 7.70 (m, 3 H), 7.39 (t, J = 8.66 Hz, 2 H), 6.00 - 5.66 (m, 1 H), 4.56 - 4.30 (m, 2 H), 3.33 (m, 2 H), 3.01 (m, 2 H), 2.36 - 2.08 (m, 4 H), 1.78 (br d, J = 5.26 Hz, 3H)

[0272] Example 48 (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylic acid [ka]

[0273] Intermediate 71 Methyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylate [ka] Methyl 1-(bromomethyl)cyclohexane-1-carboxylate (90 mg, 0.384 mmol) was added to a mixture in DMF (3 ml) of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-ol (150 mg, 0.349 mmol) (intermediate 10), sodium iodide (155 mg, 1.034 mmol), and cesium carbonate (240 mg, 0.737 mmol) while stirring. The mixture was stirred at 110°C for 16 hours, and then the reaction mixture was cooled to rt. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride aqueous solution, and then with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (Biotage Isolera, 28g NH cartridge, eluted with 15 CV of dichloromethane) yielded methyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylate (50.9 mg, 0.087 mmol, 24.97% yield) as a pale yellow powder. LCMS (Method 5): 1.02 min, m / z 583.9 [M+H]+

[0274] Preparation of (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylic acid (Example 48) [ka] A 1 mL aqueous solution of lithium hydroxide (40 mg, 1.670 mmol) was added to a 3 mL THF solution of methyl(R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylate (50.9 mg, 0.087 mmol). The mixture was stirred at 70°C for 48 hours. The reaction mixture was diluted with acetonitrile, and volatile matter was removed under reduced pressure. Purification by chromatography (Biotage Isolera, 30g C18 cartridge, 15CV, 0-20% B A, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH solution gradient elution) yielded (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylic acid (44.1 mg, 0.077 mmol, 89% yield) as a pale beige powder. LCMS (Method 5): 0.98 min, 570.2 m / z [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.16 - 12.43 (bs, 1 H), 9.12 (s, 2 H), 8.56 (br s, 1 H), 8.39 (s, 1 H), 8.16 (s, 1 H), 7.90 (dd, J = 8.77, 5.48 Hz, 2 H), 7.52 (s, 1 H), 7.34 (t, J = 8.77 Hz, 2 H), 5.63 (quin, J = 6.96 Hz, 1 H), 4.23 (s, 2 H), 2.00 (br dd, J = 11.51, 4.49 Hz, 1 H), 1.95 - 2.06 (m, 2 H), 1.69 (d, J = 7.23 Hz, 3 H), 1.38 - 1.57 (m, 6 H), 1.11 - 1.38 (m, 2 H)

[0275] Intermediate 72 2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetic acid dihydrochloride [ka] Step 1: Preparation of tert-butyl 2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetate [ka] Tert-butyl 2-bromoacetate (247 μL, 1.669 mmol) was added to a mixture of 4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazolin-8-ol (500 mg, 1.391 mmol) (intermediate 57) and potassium carbonate (456 mg, 3.30 mmol) in DMF / THF 2:1 (9 mL) while stirring. The mixture was stirred at rt for 16 hours. The reaction was quenched by the addition of formic acid (300 μL, 7.95 mmol), and volatiles were removed under reduced pressure. Purification by RP chromatography (Biotage Isolera, 60g C18 cartridge, gradient elution of solution A with 0-30% B; A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile / water 95:5 + 0.1% HCOOH) yielded tert-butyl 2-((4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetate (451 mg, 0.952 mmol, 68.5% yield) as an orange waxy substance. LCMS (Method 5): 0.66 min, 473.8 [M+H]+

[0276] Step 2: Preparation of 2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetic acid dihydrochloride [ka] Tert-butyl 2-((4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazolin-8-yl)oxy) acetate was stirred at rt for 16 hours in a 1,4-dioxane solution in 4N HCl (20 ml, 80 mmol). After removing volatile matter under reduced pressure, 2-((4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazolin-8-yl)oxy) acetate dihydrochloride (552 mg, 1.126 mmol, 81% yield) was obtained as a pale yellow powder. LCMS (Method 5): 0.45 min, 418.0 [M+H]+, 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (br t, J = 5.48 Hz, 1 H), 9.18 (s, 1 H), 8.88 (s, 2 H), 8.80 (s, 1 H), 8.41 (s, 1 H), 7.77 (d, J = 8.55 Hz, 1 H), 7.65 (d, J = 8.55 Hz, 1 H), 5.16 - 5.28 (m, 4 H), 2.63 (s, 3 H), 2.38 (s, 3 H)

[0277] Example 49 Ammonium (2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetyl)(phenylsulfonyl)amide [ka] EDCI (58.6 mg, 0.306 mmol) was added to a solution of 2-((4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy) acetate dihydrochloride (100 mg, 0.204 mmol) (intermediate 72), benzenesulfonamide (48.1 mg, 0.306 mmol), DMAP (100 mg, 0.816 mmol), and DIPEA (0.355 mL, 2.039 mmol) in DMF (2 mL) while stirring. The mixture was stirred at rt for 16 hours. The reaction was quenched by the addition of formic acid (0.115 mL, 3.06 mmol), and volatiles were removed under reduced pressure. RP chromatography (Biotage Isolera, 12 g C18 cartridge, gradient elution of solution A at 0-25% B; A: water / MeOH) was performed. Purification with 95:5 + 0.1% concentrated ammonia and B:MeOH / water 95:5 + 0.1% concentrated ammonia yielded ammonium (2-((4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetyl)(phenylsulfonyl)amide (34.8 mg, 0.061 mmol, 29.7% yield) as a white powder. LCMS (Method 5): 0.64 min, 557.1 [M+H]+, 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (br s, 1 H), 8.84 (s, 1 H), 8.80 (s, 2 H), 8.39 (s, 1 H), 8.03 (s, 1 H), 7.72 (d, J = 7.67 Hz, 2 H), 7.40 - 7.50 (m, 2 H), 7.24 - 7.34 (m, 1 H), 7.18 (br t, J = 7.45 Hz, 4 H), 4.98 (br d, J = 5.26 Hz, 2 H), 4.60 (s, 2 H), 2.55 (s, 3 H), 2.35 (s, 3 H)

[0278] Intermediate 73 2-((6-(4-fluorophenyl)-4-(((1-methylpiperidine-4-yl)methyl)amino)quinazoline-8-yl)oxy)acetate hydrochloride [ka] Step 1: Preparation of tert-butyl(6-(4-fluorophenyl)-8-hydroxyquinazoline-4-yl)((1-methylpiperidine-4-yl)methyl)carbamate [ka] A 10 mL solution of di-tert-butyl dicarbonate (1.641 mL, 7.14 mmol) in THF was added to a 20 mL solution of DIPEA (1.244 mL, 7.14 mmol) in THF while stirring. 4-dimethylaminopyridine (0.079 g, 0.649 mmol) was then added, and the mixture was stirred at rt for 16 hours. LC-MS showed complete conversion to tert-butyl(8-((tert-butoxycarbonyl)oxy)-6-(4-fluorophenyl)quinazolin-4-yl)((1-methylpiperidine-4-yl)methyl)carbamate. Volatile matter was removed under reduced pressure, and the residue was partitioned into siRNA / THF 1:1 and saturated ammonium chloride aqueous solution. The layers were separated, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was redissolved in dichloromethane (20 mL) and treated with 2.0 M dimethylamine in THF solution (4 mL). The mixture was stirred at rt for 4 hours, and then volatile matter was removed under reduced pressure. Purification by column chromatography (Biotage Isolera, 55 g NH cartridge, gradient elution of dichloromethane solution with 0-30% EtOH) yielded tert-butyl(6-(4-fluorophenyl)-8-hydroxyquinazolin-4-yl)((1-methylpiperidine-4-yl)methyl)carbamate (398 mg, 0.853 mmol, 26.3% yield) as an orange powder. LCMS (Method 5): 1.32 min, 467.4 [M+H]+

[0279] Step 2: Preparation of 2-((6-(4-fluorophenyl)-4-(((1-methylpiperidine-4-yl)methyl)amino)quinazoline-8-yl)oxy)acetate hydrochloride (intermediate 73) [ka] Tert-butyl 2-bromoacetate (0.075 mL, 0.509 mmol) was added to a solution of potassium carbonate (147 mg, 1.061 mmol) and tert-butyl (6-(4-fluorophenyl)-8-hydroxyquinazolin-4-yl)((1-methylpiperidine-4-yl)methyl)carbamate (198 mg, 0.424 mmol) in DMF (2 mL) while stirring. The mixture was stirred at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with brine (3 ×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (Biotage Isolera, 28g NH cartridge, gradient elution of 0-20% AcOEt dichloromethane solution) yielded the intermediate tert-butyl 2-((4-((tert-butoxycarbonyl)((1-methylpiperidine-4-yl)methyl)amino)-6-(4-fluorophenyl)quinazoline-8-yl)oxy) acetate. This substance was dissolved in 1,4-dioxane (3 mL) at rt and then treated with 4N HCl at rt for 18 hours. By removing volatile matter under reduced pressure, 2-((6-(4-fluorophenyl)-4-(((1-methylpiperidine-4-yl)methyl)amino)quinazoline-8-yl)oxy) acetate hydrochloride (88.1 mg, 0.191 mmol, 45.0% yield) was obtained as a pale yellow powder. LCMS (Method 5): 0.33 min, 425.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 13.95 - 14.23 (bs, 1 H), 10.65 - 10.55 (bs, 1 H), 10.11 - 10.18 (m, 1 H), 8.72 (s, 1 H), 8.53 (s, 1 H), 7.95 (br dd. - 2.90 (m, 2 H), 2.67 (s, 3 H), 2.50 - 2.53 (m, 1 H), 1.97 - 2.05 (m, 1 H), 1.90 (br d, J = 13.37 Hz, 2 H), 1.40 - 1.61 (m, 2 H)

[0280] Intermediate 74 (3-methyl-1,2,4-oxadiazole-5-yl)methylmethanesulfonate [ka] A solution of (3-methyl-1,2,4-oxadiazole-5-yl)methanol (300 mg, 2.63 mmol) and triethylamine (1.1 mL, 7.89 mmol) in DCM (6 mL) was stirred at 0°C for 5 minutes. Methanesulfonyl chloride (0.41 mL, 5.26 mmol) was added, and the reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was partitioned into DCM and water, and the two phases were separated. The aqueous phase was extracted with DCM, and the combined organic phase was passed through a liquid-phase separation filter paper. The solvent was removed under reduced pressure to obtain the title compound as an orange oil (290 mg, 57% yield). 1 H NMR (400 MHz, CDCl3): δ 4.66 (s, 2 H), 3.49 (s, 3 H), 2.43 (s, 3 H)

[0281] Intermediate 75 6-(4-fluorophenyl)-8-[(3-methyl-1,2,4-oxadiazole-5-yl)methoxy]-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine [ka] (3-methyl-1,2,4-oxadiazole-5-yl)methylmethanesulfonate (176 mg, 0.46 mmol), 6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-8-ol (150 mg, 0.23 mmol), and cesium carbonate (223 mg, 0.69 mmol) were dissolved in DMF (4 mL). The reaction mixture was heated at 55 °C for 16 hours. The reaction mixture was cooled to room temperature and then partitioned into DCM and water. The two phases were separated, and the aqueous phase was extracted with DCM (x2). The combined organic phase was concentrated under reduced pressure through liquid-phase separation filter paper. Purification by preparative HPLC yielded the title compound (78.1 mg, 75%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO): δ 9.13 (t, J = 5.9 Hz, 1 H), 8.45 (s, 1 H), 8.30 (d, J = 1.5 Hz, 1 H), 7.95-7.90 (m, 2 H), 7.75 (d, J = 1.6 Hz, 1 H), 7.59-7.49 (m, 2 H), 7.43-7.38 (m, 2 H), 5.80 (s, 2 H), 5.04 (d, J = 5.9 Hz, 2 H), 2.61-2.60 (m, 3 H), 2.39 (s, 3 H). LCMS (Method 3): [MH + ] = 458, 4.29 minutes

[0282] The following compounds were prepared by adapting the above method, starting from the substrates listed in the table. [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52]

[0283] The pharmacological activity of the compound of the present invention. In vitro electrophysiological assay of P2X3 Cells expressing the P2X3 receptor were grown according to standard procedures and maintained at 37°C in a 5% humidified CO2 atmosphere. Two days before the assay day, the cells were seeded into T175 flasks and, when grown to 80-90% confluence, were dissociated from the flasks using TrypLE. The initial cells were divided into 3 × 10⁶ cells. 6Cells were resuspended in serum-free medium at a cell density of cells / ml and packed into a Sophion Qube automated patch-clamp system. The extracellular assay buffer contained 45 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, and 10 mM HEPES at pH 7.2. The agonist stock solution was prepared in H2O and diluted with the bath solution before use. The total antagonist was prepared as a 10 mM stock solution in DMSO and diluted with the bath solution before use. All experiments were performed at room temperature under a full cell patch-clamp configuration, with 384 independent cells simultaneously voltage-fixed at -60 mV on the Sophion Qube instrument. Two baseline responses were established by applying α,β-MeATP (800 nM), and subsequent agonist applications were washed away with 0.5 U / ml apirase-containing extracellular assay buffer. After the second agonist application, the antagonist was incubated for 10 minutes in the absence of α,β-MeATP. After antagonist pre-incubation, the inhibitory effect of the antagonist was determined by co-administration of 800 nM α,β-MeATP and the antagonist. One concentration of the antagonist was evaluated in single cells, and different concentrations of the antagonist were applied to separate cells on 384 recording substrates. The control P2X3 current amplitude was taken from the peak current amplitude from the second agonist response and then pre-incubated with the antagonist. The peak P2X3 current amplitude in the presence of the antagonist was used to calculate the inhibitory effect of each antagonist concentration according to the following formula: P2X3 inhibition percentage = (P2X3 control peak amplitude - P2X3 antagonist peak amplitude) / P2X3 control peak amplitude) * 100

[0284] Concentration-response curves were constructed at 10 different concentrations, and each antagonist concentration was tested in at least two independent cells. The antagonist concentration that inhibited the P2X3 current by 50% (IC) 50 This was determined by fitting the data to the following formula: Y = a + [(ba) / (1 + 10^((log cx) d)] Here, 'a' is the minimum response, 'b' is the maximum response, and 'c' is the IC. 50 And 'd' is a hill slope.

[0285] The results for each compound are shown in Table 2 below, and are expressed as a range of activity. [Table 53] [Table 54] Here, the compounds are classified in terms of their efficacy in inhibiting P2X3 according to the following classification criteria: +++:pIC 50 h P2X3>6.5 ++:6.5 <pIC 50 h P2X3>5.5 +:5.5 <pIC 50 h P2X3>4.5

[0286] P2X 2 / 3 in vitro electrophysiological assay A representative compound of the present invention is P2X 2 / 3 We also tested the receptors. P2X 2 / 3 For the assay, the same assay protocol as the P2X3 assay was used, with two modifications: 1) 10 μM ATP was used as the agonist; and 2) the average current amplitude was measured 7 seconds after agonist application.

[0287] The results in Table 3 show that representative compounds of the present invention exhibit selective P2X 3ア To demonstrate that one is an antagonist. [Table 55] Here, the compounds are classified as P2X3 or P2X according to the following classification criteria. 2 / 3 Classify in terms of the efficacy of the isoform's inhibitory activity: +++:pIC 50 h P2X3 or h P2X 2 / 3 >6.5 ++:6.5 <pIC 50 h P2X3 or h P2X 2 / 3 >5.5 +:5.5 <pIC 50 h P2X3 or h P2X 2 / 3 >4.5

[0288] Comparative Example A N-(6-(4-fluorophenyl)chroman-4-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide [ka] The activity of compound T in comparative example A was tested using an in vitro assay for determining P2X3 receptor activity, as described above. Unlike the compound of formula (I) of the present invention, comparative example A did not show appropriate inhibitory activity against P2X3, and in fact pIC 50 The activity for the receptor P2X3, expressed as , is <4.5.

[0289] The results above, in particular, indicate that aminoquinazoline scaffolds, combined with appropriate substituents at the R2 position, unexpectedly yield a range of compounds active against the receptor P2X3. The present invention further encompasses the following embodiments. 1. Equation (I) [ka] [In the formula, X is S, SO] 2 Selected from SO or O; Z is selected from the group consisting of heteroaryls and aryls, where any of these heteroaryls and aryls may in any case (C 1 -C 3 )alkyl-, halo and (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl-; R 1 is H or (C 1 -C 4 ) is alkyl; R 2 is heteroaryl (C 1 -C 4 )alkyl-, where either such alkyl or heteroaryl is in some cases (C1 -C 3 ) alkyl, (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl and halo; R is (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-CN, (C 1 -C 6 ) Haloalkyl, -NR A R B 、(C 3 -C 8 ) Heterocycloalkyl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )heterocycloalkyl-, (C 3 -C 8 )heteroaryl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )Cycloalkyl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )Cycloalkyl-, R A O-(C 1 -C 6 )alkyl-O-(C 1 -C 6 ) alkyl-, R A NH-C(O)-(C 1 -C 4 ) alkyl-, R A R B NC(O)-(C 1 -C 4 ) alkyl-, R A OC(O)(C 1 -C 6 Selected from the group consisting of alkyl-, Here, all of these heterocycloalkyl groups are either unsubstituted or OH, -C(O)R A , -C(O)OR A 、(C 1 -C 6 ) Haloalkyl, -NH-C(O)R 1 And substituted with one or more groups selected from oxo; All of these cycloalkyls are -C(O)OR A and (C 1 -C 6 ) Substituted with one or more groups selected from haloalkyl-, In any case, (C 1 -C 6 )alkyl-, -OH and (C 3 -C 6 ) Often substituted with one or more groups selected from cycloalkyl-; R A and R B In each case, it is either H or (C 1 -C 6 )alkyl-, (C 1 -C 6 ) Haloalkyl-, -OR 1 , -SO 2 R C and (C 3 -C 6 ) Selected from the group consisting of cycloalkyls, where such cycloalkyls may have 1 or more -C(O)OR 1 Often replaced by or separately R A and R B These may, together with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered saturated heterocyclic monocyclic ring system containing a further heteroatom, which may be nitrogen or oxygen, and which may be a halo, -OR 1 It may be substituted with one or more elements selected from; R C is an arrow; However, R is (C) only when X is S or SO 1 -C 6 )alkyl- or unsubstituted (C 3 -C 8 ) It is heterocycloalkyl-. A compound of [unclear]. 2. 8-(2,2-difluoroethoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazoline-4-amine, (R)-8-(2,2-difluoroethoxy)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-6-(5-fluoropyridine-2-yl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine, (R)-8-(2,2-difluoroethoxy)-6-(5-fluoropyridine-2-yl)-N-(1-(6-methylpyridazine-3-yl)ethyl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl]quinazoline-4-amine monoenantiomer 1, 8-(2,2-difluoroethoxy)-6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl]quinazoline-4-amine monoenantiomer 2, 8-(2,2-difluoroethoxy)-N-((6-methylpyridazine-3-yl)methyl)-6-(5-methylpyridine-2-yl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-N-[(6-methylpyridazine-3-yl)methyl]-6-(5-methylpyrimidine-2-yl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine, ((R)-6-(4-fluorophenyl)-8-(morpholinosulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4amine, (Rac)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-sulfonamide, 6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)amino)quinazoline-8-sulfonamide, 6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-8-((3,3-difluoropyrrolidine-1-yl)sulfonyl)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, 8-((3,3-difluoropyrrolidine-1-yl)sulfonyl)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)quinazoline-4-amine, (R)-1-((6-(4-fluorophenyl)-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-yl)sulfonyl)piperidine-4-ol, (R)-1-((6-(4-fluorophenyl)-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-yl)sulfonyl)piperidine-4-ol, (R)-6-(4-fluorophenyl)-N-methyl-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N-methyl-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (6-(4-fluorophenyl)-N-methyl-4-((1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(piperazine-1-ylsulfonyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)-8-(piperazine-1-ylsulfonyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(methylthio)quinazoline-4-amine, 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazine-3-yl)ethyl)-8-(methylsulfinyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazine-3-yl)ethyl)-8-(oxetane-3-ylthio)quinazoline-4-amine, 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazine-3-yl)ethyl)-8-(oxetane-3-ylsulfinyl)quinazoline-4-amine, (1-((S)-3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)pyrrolidine-1-yl)ethane-1-one, (1-((R)-3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)pyrrolidine-1-yl)ethane-1-one, N-((1S,4s)-4-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)cyclohexyl)acetamide, 6-(4-fluorophenyl)-8-((1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, 3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)pyrrolidine-2-one, (R)-1-(4-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)piperidine-1-yl)ethane-1-one, (R)-1-(4-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)piperidine-1-yl)ethane-1-one, (R)-3-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)oxetan-3-ol, (R)-5-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)isoxazole-3-ol, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetic acid, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)-N-(phenylsulfonyl)acetamide, (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid, Methyl 1-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylate, Methyl(R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylate, (R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylic acid, (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylic acid, Ethyl(1S,2R)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylate, (R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylate hydrochloride, (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylic acid, Ammonium (2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetyl)(phenylsulfonyl)amide, 6-(4-fluorophenyl)-8-[(3-methyloxetane-3-yl)methoxy]-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-[[1-(trifluoromethyl)cyclopropyl]methoxy]quinazoline-4-amine, tert-butyl3-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxyazetidine-1-carboxylate, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxyacetonitrile, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxy-N-methoxy-N-methylacetamide, 2-[2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxyethoxy]ethanol, 3-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxy-1-methylpyrrolidine-2-one, 6-(4-fluorophenyl)-N-[(6-methylpyridazine-3-yl)methyl]-8-(oxazole-2-ylmethoxy)quinazoline-4-amine, 6-(4-fluorophenyl)-8-[(5-methyl-1,2,4-oxadiazole-3-yl)methoxy]-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 8-[(3-ethyl-1,2,4-oxadiazole-5-yl)methoxy]-6-(4-fluorophenyl)-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 8-[(5-cyclopropyl-1,3,4-thiadiazole-2-yl)methoxy]-6-(4-fluorophenyl)-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxy-N-(2,2,2-trifluoroethyl)acetamide, 8-((5-cyclopropyl-1,3,4-oxadiazole-2-yl)methoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine, 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)-8-(oxetane-3-yloxy)quinazoline-4-amine, Methyl 4-[[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxymethyl]piperidine-1-carboxylate, Methyl 4-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxypiperidine-1-carboxylate, Methyl 3-[[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxymethyl]piperidine-1-carboxylate, Methyl 3-[[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxymethyl]pyrrolidine-1-carboxylate, Methyl 3-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxypyrrolidine-1-carboxylate Selected from the group consisting of, formula ( I ) compounds 。 3. X is selected from S or SO; Z is an aryl, where such an aryl can be (C 1 -C 3 )alkyl-, halo and (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl-; R 1 is H or (C 1 -C 4 ) is alkyl; R 2 is heteroaryl (C 1 -C 4 )alkyl-, where either such alkyl or heteroaryl is in some cases (C 1 -C 3 ) alkyl, (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl and halo; R is (C 1 -C 6 )alkyl- and (C 3 -C 8 Selected from the group consisting of heterocycloalkyl- Therefore, item 1 formula ( I ) compounds 。 4. X is O, and equation Ia [ka] [In the formula, Z is selected from the group consisting of heteroaryls and aryls, where any of these heteroaryls and aryls may be (C 1 -C 3 )alkyl-, halo and (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl-; R 1 is H or (C 1-C 4 ) is alkyl; R 2 is heteroaryl (C 1 -C 4 )alkyl-, where either such alkyl or heteroaryl is in some cases (C 1 -C 3 ) alkyl, (C 1 -C 6 ) may be substituted with one or more groups selected from haloalkyl and halo; R is (C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-CN, (C 1 -C 6 ) Haloalkyl, -NR A R B 、(C 3 -C 8 ) Heterocycloalkyl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )heterocycloalkyl-, (C 3 -C 8 )heteroaryl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )Cycloalkyl-(C 1 -C 6 )alkyl-, (C 3 -C 8 )Cycloalkyl-, R A O-(C 1 -C 6 )alkyl-O-(C 1 -C 6 ) alkyl-, R A NH-C(O)-(C 1 -C 4 ) alkyl-, R A R B NC(O)-(C 1 -C 4 ) alkyl-, R A OC(O)(C 1 -C 6 Selected from the group consisting of alkyl-, Here, all of these heterocycloalkyls are -OH, -C(O)R A , -C(O)OR A 、(C 1 -C 6 ) Haloalkyl, -NH-C(O)R 1 And substituted with one or more groups selected from oxo; All of these cycloalkyls are -C(O)OR A and (C 1 -C 6 ) Substituted with one or more groups selected from haloalkyl-, In any case, (C 1 -C 6 )alkyl-, -OH and (C 3 -C 6 ) Often substituted with one or more groups selected from cycloalkyl-; R A and R B In each case, it is either H or (C 1 -C 6 )alkyl-, (C 1 -C 6 ) Haloalkyl-, -OR 1 , -SO 2 R C and (C 3 -C 6 ) Selected from the group consisting of cycloalkyls, where such cycloalkyls may have 1 or more -C(O)OR 1 Often replaced by; R C This is Ariel. A compound of formula (I) in item 1, represented by the above. 5. X is SO 2 And, formula Ib

change

Claims

1. Equation (I) 【Chemistry 1】 [In the formula, X is S, SO] ２ Selected from SO or O; Z is selected from the group consisting of heteroaryls and aryls, where any of these heteroaryls and aryls may be (C １ -C ３ )alkyl-, halo and (C １ -C ６ ) may be substituted with one or more groups selected from haloalkyl-; R １ is H or (C １ -C ４ ) is alkyl; R ２ is heteroaryl(C １ -C ４ )alkyl-, where either such alkyl and heteroaryl may optionally be substituted with one or more groups selected from (C １ -C ３ )alkyl, (C １ -C ６ )haloalkyl and halo; R is (C １ -C ６ )alkyl-, (C １ -C ６ )Alkyl-CN, (C １ -C ６ ) Haloalkyl, -NR Ａ R Ｂ , (C ３ -C ８ ) Heterocycloalkyl-(C １ -C ６ )alkyl-, (C ３ -C ８ )heterocycloalkyl-, (C ３ -C ８ )heteroaryl-(C １ -C ６ )alkyl-, (C ３ -C ８ )Cycloalkyl-(C １ -C ６ )alkyl-, (C ３ -C ８ )Cycloalkyl-, R Ａ O-(C) １ -C ６ )alkyl-O-(C １ -C ６ ) alkyl-, R Ａ NH-C(O)-(C １ -C ４ ) alkyl-, R Ａ R Ｂ N-C(O)-(C １ -C ４ ) alkyl-, R Ａ O-C(O)(C １ -C ６ ) Selected from the group consisting of alkyl-, Here, all of these heterocycloalkyl groups are either unsubstituted or OH, -C(O)R Ａ , -C(O)OR Ａ , (C １ -C ６ ) Haloalkyl, -NH-C(O)R １ And substituted with one or more groups selected from oxo; All of these cycloalkyls are -C(O)OR Ａ and (C １ -C ６ ) Substituted with one or more groups selected from haloalkyl-, In any case, (C) １ -C ６ )alkyl-, -OH and (C ３ -C ６ ) may be substituted with one or more groups selected from cycloalkyl groups; R Ａ and R Ｂ In each case, it is either H or (C １ -C ６ )alkyl-, (C １ -C ６ ) Haloalkyl-,-OR １ , -SO ２ R Ｃ and (C ３ -C ６ ) Selected from the group consisting of cycloalkyls, where such cycloalkyls may have one or more -C(O)OR １ Often replaced by or separately R Ａ and R Ｂ These may, together with the nitrogen atom to which they are bonded, form a five-membered or six-membered saturated heterocyclic monocyclic ring system containing a further heteroatom, which may be nitrogen or oxygen, and which may be a halo and -OR １ It may be substituted with one or more elements selected from; R Ｃ is an allele; However, R is (C) only when X is S or SO １ -C ６ ) alkyl- or unsubstituted (C ３ -C ８ ) It is a heterocycloalkyl compound. A compound of or a pharmaceutically acceptable salt thereof 8-(2,2-difluoroethoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine, (R)-8-(2,2-difluoroethoxy)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-6-(5-fluoropyridine-2-yl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine, (R)-8-(2,2-difluoroethoxy)-6-(5-fluoropyridine-2-yl)-N-(1-(6-methylpyridazine-3-yl)ethyl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl]quinazoline-4-amine monoenantiomer 1, 8-(2,2-difluoroethoxy)-6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl]quinazoline-4-amine monoenantiomer 2, 8-(2,2-difluoroethoxy)-N-((6-methylpyridazine-3-yl)methyl)-6-(5-methylpyridine-2-yl)quinazoline-4-amine, 8-(2,2-difluoroethoxy)-N-[(6-methylpyridazine-3-yl)methyl]-6-(5-methylpyrimidine-2-yl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine, ((R)-6-(4-fluorophenyl)-8-(morpholinosulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, (Rac)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)-8-(morpholinosulfonyl)quinazoline-4-amine, 6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)amino)quinazoline-8-sulfonamide, 6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N,N-dimethyl-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-8-((3,3-difluoropyrrolidine-1-yl)sulfonyl)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, 8-((3,3-difluoropyrrolidine-1-yl)sulfonyl)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)quinazoline-4-amine, (R)-1-((6-(4-fluorophenyl)-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-yl)sulfonyl)piperidine-4-ol, (R)-1-((6-(4-fluorophenyl)-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-yl)sulfonyl)piperidine-4-ol, (R)-6-(4-fluorophenyl)-N-methyl-4-((1-(6-methylpyridazine-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N-methyl-4-((1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)amino)quinazoline-8-sulfonamide, (6-(4-fluorophenyl)-N-methyl-4-((1-(5-methyl-1,3,4-thiadiazole-2-yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(piperazine-1-ylsulfonyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)-8-(piperazine-1-ylsulfonyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(methylthio)quinazoline-4-amine, 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazin-3-yl)ethyl)-8-(methylsulfinyl)quinazoline-4-amine, (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)-8-(oxetane-3-ylthio)quinazoline-4-amine, 6-(4-fluorophenyl)-N-((R)-1-(6-methylpyridazine-3-yl)ethyl)-8-(oxetane-3-ylsulfinyl)quinazoline-4-amine, (1-((S)-3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)pyrrolidine-1-yl)ethane-1-one, (1-((R)-3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)pyrrolidine-1-yl)ethane-1-one, N-((1S,4s)-4-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)cyclohexyl)acetamide, 6-(4-fluorophenyl)-8-((1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, 3-((6-(4-fluorophenyl)-4-(((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)pyrrolidine-2-one, (R)-1-(4-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazolin-8-yl)oxy)piperidine-1-yl)ethane-1-one, (R)-6-(4-fluorophenyl)-8-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxy)-N-(1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)quinazoline-4-amine, (R)-3-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)oxetan-3-ol, (R)-5-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)isoxazole-3-ol, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetic acid, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)-N-(phenylsulfonyl)acetamide, (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid, Methyl 1-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylate, Methyl(R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylate, (R)-1-(2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopropane-1-carboxylic acid, (1R,2S)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylic acid, Ethyl(1S,2R)-2-(2-((6-(4-fluorophenyl)-4-(((6-methylpyridazine-3-yl)methyl)amino)quinazoline-8-yl)oxy)acetamide)cyclopentan-1-carboxylate, (R)-4-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)piperidine-4-carboxylate hydrochloride, (R)-1-(((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)amino)quinazoline-8-yl)oxy)methyl)cyclohexane-1-carboxylic acid, Ammonium (2-((4-(((6-methylpyridazine-3-yl)methyl)amino)-6-(5-methylpyrimidine-2-yl)quinazoline-8-yl)oxy)acetyl)(phenylsulfonyl)amide, 6-(4-fluorophenyl)-8-[(3-methyloxetan-3-yl)methoxy]-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-[[1-(trifluoromethyl)cyclopropyl]methoxy]quinazoline-4-amine, tert-butyl 3-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxyazetidine-1-carboxylate, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxyacetonitrile, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxy-N-methoxy-N-methylacetamide, 2-[2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxyethoxy]ethanol, 3-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxy-1-methylpyrrolidine-2-one, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(oxazole-2-ylmethoxy)quinazoline-4-amine, 6-(4-fluorophenyl)-8-[(5-methyl-1,2,4-oxadiazole-3-yl)methoxy]-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 8-[(3-ethyl-1,2,4-oxadiazole-5-yl)methoxy]-6-(4-fluorophenyl)-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 8-[(5-cyclopropyl-1,3,4-thiadiazole-2-yl)methoxy]-6-(4-fluorophenyl)-N-[(6-methylpyridazine-3-yl)methyl]quinazoline-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxy-N-(2,2,2-trifluoroethyl)acetamide, 8-((5-cyclopropyl-1,3,4-oxadiazole-2-yl)methoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazine-3-yl)methyl)quinazoline-4-amine, Methyl 4-[[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxymethyl]piperidine-1-carboxylate, Methyl 4-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxypiperidine-1-carboxylate, Methyl 3-[[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxymethyl]piperidine-1-carboxylate, Methyl 3-[[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazoline-8-yl]oxymethyl]pyrrolidine-1-carboxylate and Methyl 3-[6-(4-fluorophenyl)-4-[(6-methylpyridazine-3-yl)methylamino]quinazoline-8-yl]oxypyrrolidine-1-carboxylate A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

2. A pharmaceutical composition comprising a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more active ingredients, mixed with one or more pharmaceutically acceptable carriers or additives.

3. A pharmaceutical composition according to claim 2 for oral administration.

4. P2X ３ A pharmaceutical composition according to claim 2 or 3 for the treatment of any disease involving receptors.

5. A pharmaceutical composition according to claim 2 or 3 for the prevention and / or treatment of a respiratory disease selected from cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, postviral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).

6. The pharmaceutical composition according to claim 5, wherein the cough is associated with respiratory diseases such as COPD, asthma, and bronchospasm.

7. A pharmaceutical composition according to claim 2 or 3 for the prevention and / or treatment of chronic cough.

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