Pyrimidopyridine derivatives as p2x3 inhibitors

Abstract

The present invention relates to compounds of Formula I (hereinafter referred to as P2X3 inhibitors) that inhibit P2X purinergic receptor 3; in particular, the present invention relates to compounds that are pyridopyrimidine derivatives, methods of making such compounds, pharmaceutical compositions containing them and therapeutic uses thereof. The compounds of the present invention are useful in the treatment of a number of disorders associated with P2X3 receptor mechanisms, such as respiratory diseases, including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

Description

Invention Field

[0001] This invention relates to compounds that inhibit P2X purine receptor 3 (hereinafter referred to as P2X3 inhibitors); in particular, this invention relates to compounds that are pyridopyrimidine derivatives, methods for preparing such compounds, pharmaceutical compositions comprising them, and their therapeutic uses.

[0002] The compounds of this invention can be used to treat many disorders associated with the P2X3 receptor mechanism, such as respiratory diseases, including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). Background of the Invention

[0004] P2X receptors are cell surface ion channels activated by extracellular adenosine triphosphate (ATP). The P2X receptor family consists of a trimeric assembly of seven distinct subunit isoforms (P2X1-7), which assemble into homomeric and heteromeric channels. All subunits share a common topology containing intracellular terminals, two transmembrane helices forming the ion channel, and a large extracellular domain containing an ATP-binding site. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X7 channels... 2 / 3 and P2X 1 / 5The channels have been fully characterized following heterologous expression. P2X receptors are widely distributed and functional responses are observed in neurons, glial cells, epithelium, endothelium, bone, muscle, and hematopoietic tissues. In smooth muscle, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., during ejaculation). In sensory nerves, they are involved in the initiation of afferent signals in multiple viscera (e.g., bladder, intestine) and play a key role in sensing tissue damage and inflammatory stimuli. Paracrine effects of ATP signaling via P2X receptors may be present in the neurohypophysis, ductal glands, airway epithelium, kidney, bone, and hematopoietic tissues (RA. North: Molecular Physiology of P2X Receptors; Physiol Rev, Vol. 82, October 2002). All P2X receptors are non-selective cation channels permeable to Na+ and Ca+ ions and activated by ATP; however, receptor subtypes differ in their pharmacology regarding sensitivity to ATP and small molecule antagonists (KKaczmarek-Hajek et al.: Molecular and functional properties of P2X receptors - recent progress and persisting challenges; Purinergic Signalling 8:375-417, 2012).

[0005] In humans, P2X3 receptors have been reported at the mRNA level in the heart and spinal cord, and at the protein level in the DRG, gut (intestinal plexus neurons), bladder (urinary tract epithelium and lower urinary tract epithelium), and dental pulp (Garcia-Guzman M et al.: Molecular characterization and pharmacological properties of the human P2X3 purinoceptor: Brain Res Mol Brain Res. 1997; 47(1-2): 59-66).

[0006] The neurophysiological role of P2X3 receptors in the sensory nerve function of the airway is similar to that mediating the neurophysiological role of somatic nociception (Undem BJ and Nassenstein C: Airway nerves and dyspnea associated with inflammatory airway disease, Respir Physiol Nerobiol 167:36-44, 2009). This similarity has fueled the hypothesis that P2X3 receptors are involved in the symptoms of airway dysfunction, including cough and bronchial hyperresponsiveness (Ford AP: In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization, Purinergic signal 8(Supplement 1):3-26, 2012; North RA, Jarvis MF P2X Receptors as Drug Targets; Mol Pharmacol, 83:759-769, 2013). The P2X3 subunit is also colocalized in many neurons, especially in the DRG, nodal ganglion, 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):368-3822002).

[0007] 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).

[0008] P2X3 and P2X 2 / 3 Channels play an important role in the development of arthritic hyperalgesia in arthritic joints (Teixeira JM et al.: P2X3 and P2X). 2 / 3Receptors Play a Crucial Role in Articular HyperalgesiaDevelopment Through Inflammatory Mechanisms in the Knee Joint ExperimentalSynovitis, Mol Neurobiol Oct; 54(8):6174-6186, 2017).

[0009] P2X3 is also a potential target for the therapeutic management of bladder pain. They have also been proposed as analgesic targets for the treatment of ureteral colic and to promote the expulsion 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).

[0010] P2X3 overexpression is 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).

[0011] It has been proposed that P2X3 antagonists can improve the recovery of erectile function (Li CL et al.: Effects of intracavernous injection of P2X3 and NK1 receptor antagonists on erectiledysfunction induced by spinal cord transection in rats, Andrologia. Feb; 47(1):25-9, 2015).

[0012] ATP enhances citrate-induced and histamine-induced cough in preclinical models, an effect that 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 reflexsensitivity in guinea pigs, https: / / www.ncbi.nlm.nih.gov / pubmed / 16935279Oct10;547(1-3):160-4,2006). In humans, local delivery of ATP triggers 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).

[0013] The therapeutic potential of P2X3 antagonists for treating chronic cough was first recognized by Ford and Undem (Ford AP, Undem BJ: The therapeutic promise of ATP antagonism at P2X3 receptors inrespiratory and urological disorders, Front Cell Neurosci, Dec 19; 7:267, 2013). P2X3 is expressed by airway afferent nerves and mediates the hypersensitivity response of the cough reflex, which is significantly reduced by oral administration of the 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).

[0014] ATP is a key neurotransmitter in the taste system, primarily mediated by P2X. 2 / 3Heteromeric receptors play a role. Therefore, disruption of taste function may be an undesirable consequence of trials using purinergic P2X3 antagonists to treat 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 rattaste buds, Neuroreport, 10(5):1107-11, 1999).

[0015] Several compounds have been described in the literature as P2X3 and / or P2X. 2 / 3 Inhibitors.

[0016] WO2017058645 (Afferent Pharmaceuticals INC) discloses diaminopyrimidine P2X3 / P2X 2 / 3 Antagonists are used to treat disorders including cough, chronic cough, and cough urge (including cough associated with respiratory diseases or disorders), including administration of an effective amount of the disclosed compound. However, pyridopyrimidine derivatives are not disclosed.

[0017] WO2017011729 (Patara Pharma LLC) discloses cromoglycine (cromolyn) or a pharmaceutically acceptable salt thereof and P2X3 and / or P2X. 2 / 3 Receptor antagonists are used as antitussives to treat lung diseases and conditions.

[0018] WO2016091776 (Evotec AG) discloses 1,3-thiazol-2-yl-substituted benzamide compounds that inhibit the P2X3 receptor and pharmaceutical compositions containing such compounds, as well as the use of the compounds for the treatment of several disorders, including respiratory diseases.

[0019] WO2016088838 (Shionogi) disclosed new P2X3 and / or P2X 2 / 3 Purine derivative compounds with receptor antagonistic effects.

[0020] WO2016084922, (Shionogi) disclosed new P2X3 and / or P2X2 / 3 Triazine derivative compounds with receptor antagonistic effects.

[0021] WO2008123963 (Renovis) relates to fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions comprising such compounds. Methods for the prevention and / or treatment of several disorders, such as neurodegenerative disorders, pain, asthma, and autoimmune disorders, are also provided, comprising administering the disclosed compounds.

[0022] WO2008130481 (Renovis) discloses tetrahydropyrido[4,3-d]pyrimidine 2-cyanophenyl fused heterocyclic compounds and pharmaceutical compositions comprising such compounds.

[0023] WO2010033168 (Renovis) discloses a series of benzamides substituted with phenyl or pyridyl groups, which are claimed to be useful for treating diseases associated with P2X purinergic receptors, especially P2X3 receptors and / or P2X. 2 / 3 Receptor antagonists. However, no pyridopyrimidine derivatives have been disclosed.

[0024] WO2009110985 (Renovis) relates to phenyl- and pyridyl-substituted benzamide compounds and pharmaceutical compositions comprising such compounds, but does not relate to thiazole-substituted benzamides, thus making the compounds different from those of the present invention.

[0025] WO2008000645 (Roche) disclosed P2X3 and / or P2X. 2 / 3 Tetraazole-substituted aryl amide antagonists for receptors can be used to treat genitourinary pain, gastrointestinal and respiratory diseases, symptoms and disorders.

[0026] In many therapeutic areas, particularly respiratory diseases, there is still ongoing development of new and pharmacologically improved P2X3 and / or P2X. 2 / 3 The potential of inhibitors.

[0027] Despite the prior art cited above, there remains a need for novel pyridopyrimidine compounds, preferably with selective action on the P2X3 receptor, for the treatment of diseases associated with the P2X3 receptor, in many therapeutic areas, such as respiratory diseases in particular.

[0028] It is worth noting that the prior art does not describe or suggest pyridinidine derivative compounds of general formula (I) of the present invention that represent the solutions required above. Summary of the Invention

[0029] This invention relates to compounds of formula (I).

[0030]

[0031] Where X1, X2, and X3 are independently CH or N,

[0032] Z is H or selected from (C1-C4) alkyl, heteroaryl, aryl, wherein any of such heteroaryl and aryl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halo, CN, (R A R B Substitution of NC(O)- groups;

[0033] R1 is H;

[0034] R2 is selected from heteroaryl (C1-C4)alkyl-, (C3-C8)heterocyclic alkyl-, (C1-C6)alkyl-, wherein any one of such alkyl, heteroaryl, and heterocyclic alkyl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halogenated, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, R A O- groups are substituted;

[0035] R A and R B Each time it appears, it is independently H or (C1-C4) alkyl-, or

[0036] R A and R B They can form a 6-membered saturated heterocyclic monocyclic ring system together with the nitrogen atoms to which they are attached, which optionally contains another heteroatom of nitrogen, and which can optionally be R C (O)C-substitution;

[0037] R C It is a (C1-C6) alkyl group;

[0038] J is H or (R) A R B )N-.

[0039] In a second aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more other active ingredients, mixed with one or more pharmaceutically acceptable carriers or excipients.

[0040] In a third aspect, the present invention provides a compound of formula (I) for use as a medicament.

[0041] In another aspect, the present invention provides the use of compounds of formula (I) for treating any disease in which the P2X3 receptor is involved.

[0042] In another aspect, the present invention relates to compounds of formula (I) for the prevention and / or treatment of respiratory diseases, including cough, subacute or chronic cough, treatment resistance 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.

[0043] In another aspect, the present invention relates to compounds of formula IIIa.

[0044]

[0045] Where X is N or CH.

[0046] R7 is OH and / or Cl;

[0047] R8 is halogenated.

[0048] In another aspect, the present invention relates to the use of compounds of formula (IIIa) as intermediates in the preparation of compounds of formula (I). Invention Details

[0050] This invention relates to compounds of formula (I).

[0051]

[0052] Where X1, X2, and X3 are independently CH or N,

[0053] Z is H or selected from (C1-C4) alkyl, heteroaryl, aryl, wherein any of such heteroaryl and aryl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halogen, CN, (R A R B Substitution of NC(O)- groups;

[0054] R1 is H;

[0055] R2 is selected from heteroaryl (C1-C4)alkyl-, (C3-C8)heterocyclic alkyl-, (C1-C6)alkyl-, wherein any one of such alkyl, heteroaryl, and heterocyclic alkyl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halogenated, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, R A O- groups are substituted;

[0056] R A and R B Each time it appears, it is independently H or (C1-C4) alkyl-, or

[0057] R A and R B They can form a 6-membered saturated heterocyclic monocyclic ring system together with the nitrogen atoms to which they are attached, which optionally contains another heteroatom of nitrogen, and which can optionally be R C (O)C-substitution;

[0058] R C It is a (C1-C6) alkyl group;

[0059] J is H or selected from (R) A R B )N-.

[0060] definition

[0061] The term “pharmaceutically acceptable salt” used in this article refers to a derivative of a compound of formula (I), wherein the parent compound is suitably modified by converting any free acidic or basic group present therein into the corresponding addition salt with any base or acid that is conventionally considered pharmaceutically acceptable.

[0062] Suitable examples of the salt may therefore include inorganic or organic acid addition salts with basic residues such as amino groups and inorganic or organic base addition salts with acidic residues such as carboxyl groups.

[0063] The cations of inorganic bases that can be suitably used to prepare salts include ions of alkali metals or alkaline earth metals (such as potassium, sodium, calcium, or magnesium).

[0064] Salts obtained by reacting a primary compound that acts as a base with an inorganic or organic acid to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, and citric acid.

[0065] The term "halogen" or "halogen atom" as used herein includes fluorine, chlorine, bromine, and iodine atoms, preferably chlorine or fluorine.

[0066] The term "(C)" x -C y "alkyl" (where x and y are integers) means a straight-chain or branched alkyl residue having x to y carbon atoms. Thus, for example, when x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0067] The term "(C)" used in this article x -C y Alkylene (where x and y are integers) represents a C group having two unsaturated valences. x -C yAlkyl residues, such as divalent methylene residues.

[0068] The expression "(C x -C y ) haloalkyl (where x and y are integers) represents the "C" defined above. x -C y An alkyl group, wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different.

[0069] The "(C)" x -C y Examples of "halogenated alkyl" groups can therefore include halogenated, polyhalogenated, and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl or difluoromethyl, trifluoroethyl.

[0070] By analogy, 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 hydroxyl (OH) or amino groups, respectively. Examples include hydroxymethyl, aminomethyl, dimethylaminopropyl, etc.

[0071] In this specification, unless otherwise provided, aminoalkyl refers to compounds containing one or more amino groups (-NR). A R B Aminoalkyl groups are substituted alkyl groups (i.e., "(C1-C6)alkyl" groups). Thus, an example of an aminoalkyl group is a monoaminoalkyl group such as R... A R B N-(C1-C6)alkyl.

[0072] Regarding the substituent R as defined above and below A and R B When R A and R B When forming 5-6 membered heterocyclic residues together with the nitrogen atoms they are attached to, at least one other ring carbon atom in the heterocyclic residue is optionally substituted with at least one heteroatom (e.g., N, S, or O) and / or may have an oxo (=O) substituent. It should be understood that the heterocyclic residue may further optionally be substituted at any available position in the ring (i.e., on a carbon atom, or on any heteroatom that can be substituted). Substitution on a carbon atom includes spirodisubstituted and substitution on two adjacent carbon atoms, thus forming an additional 5-6 membered heterocycle in both cases. Examples of such heterocyclic residues are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, piperazine-4-yl-2-one, 4-morpholinyl, morpholinyl-3-one, and 1-(piperazin-1-yl)ethenone.

[0073] The term "(C)" x -C y "(cycloalkyl)" (where x and y are integers) represents a saturated cyclic hydrocarbon group containing a specified number of cyclic carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0074] The term "aryl" refers to a monocyclic carbon ring system having six ring atoms, wherein the ring is an aromatic ring. Suitable examples of aryl monocyclic ring systems include, for example, the phenyl group.

[0075] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic residue containing one or more heteroatoms selected from S, N, and O, and includes residues having two such monocyclic rings, or one such monocyclic ring and a monocyclic aryl ring (fused together by a common bond). Suitable examples of 5- or 6-membered heteroaryls are: thienyl, furanyl, pyrroleyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, etc. azole group, iso Azolyl, isothiazolyl, triazolyl, thiadiazolyl Diazolyl, pyridyl, pyridinyl, pyrazinyl, tetrazolyl, and triazinyl.

[0076] The term "heterocyclic group" or "heterocycle" refers to a saturated monocyclic, bicyclic, or tricyclic nonaromatic residue containing one or more heteroatoms selected from S, N, and O. In the case of bicyclic heterocyclic systems, the scope of this term includes fused, spirocyclic, and bridged bicyclic systems.

[0077] The term "(C)" x -C y Heterocyclic alkyl groups (where x and y are integers) represent saturated or partially unsaturated monocyclic alkyl groups (C1-C2). x -C y A cycloalkyl group, wherein at least one ring carbon atom is substituted by at least one heteroatom (e.g., N, S, or O) or may have an oxo (=O) substituent. The heterocycloalkyl group (i.e., a heterocyclic residue or group) may further optionally be substituted at available positions in the ring (i.e., on a carbon atom, or on a heteroatom that can be substituted). Substitution on a carbon atom includes spirodisubstituted substitution and substitution on two adjacent carbon atoms, thus forming an additional fused 5-6 membered heterocycle in both cases. (C) x -C y Examples of heterocyclic alkyl groups include: pyrrolidinyl, imidazoalkyl, thiazoalkyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl or tetrahydropyridinyl, tetrahydrothiopheneyl, azahexacyclic butyl, oxohexacyclic butyl, tetrahydropyranyl, pyranyl, 2H-pyranyl or 4H-pyranyl, dihydrofuranyl or tetrahydrofuranyl, dihydroisocyanoyl... Azolyl, pyrrolidone-2-one-yl, dihydropyrrolyl residues, etc.

[0078] Specific examples of the heterocyclic residues are tetrahydrothiophene 1,1-dioxide, 3,3-difluoropyrrolidinyl, 1-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl.

[0079] The terms "aryloxy" and "aryl(C1-C6)alkoxy," as well as "heteroaryloxy" and "heteroaryl(C1-C6)alkoxy," indicate aryl or heteroaryl groups linked by an oxygen bridge and a chain of aryl-alkoxy or heteroaryl-alkoxy groups. Examples of such groups are phenoxy, benzyloxy, and pyridyloxy, respectively.

[0080] The term "aryl (C1-C6) alkyl" refers to an aryl ring attached to a straight-chain or branched alkyl group, wherein the number of carbon atoms is 1-6, such as phenylmethyl (i.e., benzyl), phenylethyl, or phenylpropyl.

[0081] Terminology (C) z -C k Heterocyclic alkyl-(C x -C y Alkyl (where z and k are integers) represents a heterocycle that is attached to a straight-chain or branched alkyl group having x to y carbon atoms.

[0082] Similarly, the term "heteroaryl (C)" x -C y alkyl or aryl (C x -C y "alkyl" indicates a heteroaryl or aryl ring attached to a straight-chain or branched alkyl group having x to y carbon atoms.

[0083] The term "cyclic system" refers to a monocyclic, bicyclic, or polycyclic cyclic system, which can be saturated, partially unsaturated, or unsaturated, such as aryl, (C3-C4) ring systems. 10 (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl or heteroaryl.

[0084] The terms “group,” “residue,” “segment,” or “substituent” are synonymous and intended to indicate a functional group or molecular segment that can be linked to a bond or other segment or molecule. Thus, as an example, “heterocyclic residue” herein refers to a monocyclic or bicyclic saturated or partially saturated heterocyclic portion (group, residue), preferably a 4-11 membered monocyclic residue, wherein at least one other ring carbon atom in the heterocyclic residue is optionally substituted by at least one other heteroatom independently selected from N, S, or O and / or may have an oxo (=O) substituent, the heterocyclic residue further optionally including spirodisubstituted and substitutions on two adjacent or vicinal atoms forming another 5-6 membered ring or heterocyclic, saturated, partially saturated, or aromatic ring. Examples of such heterocyclic residues are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, etc.

[0085] A dash ("-") not between two letters or symbols is intended to represent the connection point of a substituent. When represented graphically, connection points in cyclic functional groups are indicated by a dot ("·") located in one of the available ring atoms, where the functional group can be attached to a bond or other segment of the molecule.

[0086] The oxidative moiety is represented by (O), as an alternative to other common representations, such as (=O). Thus, for the purposes of the general formula, the carbonyl group is represented herein as -C(O)-. Generally, groups enclosed in parentheses are side groups, not included in the chain, and are used where deemed useful to help eliminate ambiguity in straight-chain chemical formulas; for example, sulfonyl-SO2- may also be represented as -S(O)2- to eliminate ambiguity, for example, regarding sulfinyl-S(O)O-.

[0087] Whenever a basic amino or quaternary ammonium group is present in a compound of formula I, a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pyrate, and naphthalenedisulfonate. Similarly, in the presence of an acidic group such as a COOH group, a corresponding physiologically acceptable cation salt may also be present, for example, including alkali metal or alkaline earth metal ions.

[0088] It is obvious that the compound of formula (I) can exist as an optical stereoisomer when it contains one or more stereocenters.

[0089] When compounds according to the invention have at least one stereocenter, they may correspondingly exist as enantiomers. When compounds according to the invention have two or more stereocenters, they may additionally exist as diastereomers. All such single enantiomers, diastereomers, and mixtures thereof in any proportion are covered within the scope of this invention. The absolute configuration (R) or (S) of the carbon with the stereocenter is specified based on the Cahn-Ingold-Prelog nomenclature rule, which prioritizes functional groups.

[0090] The present invention further relates to the corresponding deuterated derivatives of the compounds of formula (I).

[0091] All preferred combinations or embodiments of the compounds of Formula I described above and below can be combined with each other and are equally applicable after necessary modifications to the details.

[0092] In a preferred embodiment, the present invention relates to compounds of formula (I) as defined above, wherein

[0093] X1, X2, and X3 are independently CH or N.

[0094] Z is selected from

[0095] Heteroaryl, preferably pyridyl, thiazolyl, and thiophene, and

[0096] Aryl, preferably phenyl

[0097] Any of such heteroaryl and aryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl and halogenated, preferably selected from methyl, fluorine and chlorine groups;

[0098] R1 is H;

[0099] R2 is a heteroaryl (C1-C4) alkyl-, preferably (pyridazyl)methyl, (pyridazyl)ethyl, (pyridyl)methyl, (pyrimidinyl)ethyl, (pyrimidinyl)ethyl, ( (diazolyl)ethyl, wherein any of such heteroaryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl, haloalkyl and (C1-C6) haloalkyl, preferably selected from methyl, fluorine and trifluoromethyl; and

[0100] J is H.

[0101] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 1 below and their pharmaceutically acceptable salts.

[0102] Table 1: List of preferred compounds having formula (I)

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] In a preferred embodiment, the present invention relates to compounds of formula (I) as defined above, represented by formula (Ia), wherein X1 is N, and X2 and X3 are CH.

[0113]

[0114] Z is H or selected from (C1-C4) alkyl, heteroaryl, aryl, wherein any of such heteroaryl and aryl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halogen, CN, (R A R B Substitution of NC(O)- groups;

[0115] R1 is H;

[0116] R2 is selected from heteroaryl (C1-C4)alkyl-, (C3-C8)heterocyclic alkyl- (C1-C6)alkyl, wherein any one of such alkyl or heteroaryl groups may optionally be replaced by one or more groups selected from (C1-C3) alkyl, halogenated, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, R A O- groups are substituted;

[0117] R A and R B Each time it appears, it is independently H or (C1-C4) alkyl-, or

[0118] R A and R B They can form a 6-membered saturated heterocyclic monocyclic ring system together with the nitrogen atoms to which they are attached, which optionally contains another heteroatom of nitrogen, and which can optionally be R C (O)C-substitution;

[0119] R C It is a (C1-C6) alkyl group;

[0120] J is H or (R) A R B )N-.

[0121] In another preferred embodiment, the present invention relates to a compound of formula (Ia), wherein

[0122] Z is H or selected from

[0123] (C1-C4)alkyl-, preferably methyl,

[0124] (R A R B )N-, where R A It is H and R B It is a phenyl group, which is optionally further substituted with one or more fluorine molecules;

[0125] The heteroaryl group is pyridyl, thiazolyl, or thiophene, each of which is further optionally substituted by one or more groups selected from methyl or chlorine;

[0126] Aryl, preferably phenyl, each of which is further optionally surrounded by one or more molecules selected from methyl, fluorine, CN, and (R) A R B )NC(O)-(where R A and R B It is the substitution of H groups;

[0127] R1 is H;

[0128] R2 is selected from

[0129] Heteroaryl (C1-C4)alkyl-, preferably (pyridazinyl)methyl, (pyridazinyl)ethyl, (pyridinyl)methyl, (pyridinyl)ethyl, (pyrimidinyl)ethyl, ( (diazolyl)ethyl,

[0130] Heteroaryl (C1-C6)alkoxy, preferably pyridyloxy,

[0131] Heteroaryl-(C1-C6)hydroxyalkyl, preferably (pyridyl)ethanol,

[0132] (C3-C8)heterocyclic alkyl-(C1-C6)alkyl, preferably (morpholinyl)ethyl,

[0133] Each of the heteroaryl groups is optionally replaced by one or more molecules selected from methyl, fluorine, trifluoromethyl, R A O-(where R) A It is a group substitution of methyl groups;

[0134] J is H or (R) A R B )N-, where R A and R B Together with the nitrogen atoms to which they are attached, they form a 6-membered saturated heterocyclic monocyclic ring system, which optionally contains another heteroatom of nitrogen, and the heterocyclic residues are optionally further converted to R C (O)C-(where R) C (It is a methyl) substitution.

[0135] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 2 below and their pharmaceutically acceptable salts.

[0136] Table 2: List of preferred compounds having formula (Ia)

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] In a still preferred embodiment, the present invention relates to compounds of formula (Ia), wherein

[0150] Z is selected from heteroaryl and aryl, wherein any one of such heteroaryl and aryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl and halogenated groups;

[0151] R1 is H;

[0152] R2 is selected from heteroaryl (C1-C4) alkyl, wherein any one of such alkyl or heteroaryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl, halo, (C1-C6) haloalkyl, or oxo groups;

[0153] J is H.

[0154] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 3 below and their pharmaceutically acceptable salts.

[0155] Table 3: List of preferred compounds having formula (Ia)

[0156]

[0157]

[0158]

[0159]

[0160] In another preferred embodiment, the present invention relates to a compound of formula (Ia), wherein

[0161] Z is selected from phenyl, pyridyl and thiophene, wherein any one of such phenyl, pyridyl and thiophene may optionally be substituted by one or more groups selected from methyl and fluorine;

[0162] R1 is H;

[0163] R2 is selected from heteroaryl (C1-C2) alkyl groups, wherein any one of such heteroaryl groups may optionally be substituted by one or more groups selected from methyl, fluorine and trifluoromethyl groups;

[0164] J is H.

[0165] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 4 below and their pharmaceutically acceptable salts.

[0166] Table 4: List of further preferred compounds having formula (Ia)

[0167]

[0168]

[0169]

[0170] In a still preferred embodiment, the present invention relates to compounds of formula (I) as defined above, represented by formula Ib, wherein X1 is CH,

[0171]

[0172] Where X2 and X3 are independently CH or N,

[0173] Z is selected from heteroaryl and aryl, wherein any one of such aryl and heteroaryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl or halogenated groups;

[0174] R1 is H;

[0175] R2 is selected from heteroaryl (C1-C4) alkyl-, wherein any one of such alkyl and heteroaryl groups may optionally be substituted by one or more groups selected from (C1-C3) alkyl and (C1-C6) haloalkyl groups;

[0176] J is H.

[0177] In another preferred embodiment, the present invention relates to compounds of formula Ib, wherein X2 and X3 are independently CH or N.

[0178] Z is selected from

[0179] The heteroaryl group, which is pyridyl or thiazolyl, each of which is optionally further substituted with one or more methyl groups.

[0180] Aryl group, which is phenyl, each of which is further optionally substituted with one or more fluorine groups;

[0181] R1 is H;

[0182] R2 is selected from

[0183] Heteroaryl (C1-C4)alkyl-, which are (pyrimidinyl)ethyl, (pyridazinyl)methyl, ( (diazolyl)ethyl,

[0184] Each of the heteroarylalkyl groups is further optionally substituted with one or more groups selected from methyl and trifluoromethyl;

[0185] J is H.

[0186] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 5 below and their pharmaceutically acceptable salts.

[0187] Table 5: List of preferred compounds having formula (Ib)

[0188]

[0189]

[0190] In another preferred embodiment, the present invention relates to compounds of formula Ib, wherein X2 and X3 are independently CH or N.

[0191] Z is selected from pyridyl, thiazolyl, and phenyl.

[0192] Each of the pyridyl, thiazolyl, and phenyl groups is optionally substituted with one or more groups selected from methyl and fluorine;

[0193] R1 is H;

[0194] R2 is selected from (pyrimidinyl)ethyl and (pyridazinyl)methyl.

[0195] Each of the (pyrimidinyl)ethyl and (pyridazinyl)methyl groups is optionally substituted with one or more groups selected from methyl and trifluoromethyl groups;

[0196] J is H.

[0197] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 6 below and their pharmaceutically acceptable salts.

[0198] Table 6: List of preferred compounds having formula (Ib)

[0199]

[0200] In a still preferred embodiment, the present invention relates to compounds of formula (I) as defined above, represented by formula Ic, wherein X1 and X3 are N and X2 is CH.

[0201]

[0202] Z is selected from aryl and heteroaryl groups, wherein any one of such aryl and heteroaryl groups may optionally be substituted by one or more groups selected from halogenated and (C1-C3) alkyl groups;

[0203] R1 is H;

[0204] R2 is selected from heteroaryl (C1-C4)alkyl-, wherein any of such heteroaryl groups may optionally be substituted by one or more groups selected from (C1-C3)alkyl, (C1-C6) haloalkyl;

[0205] J is H.

[0206] In another preferred embodiment, the present invention relates to compounds of formula Ic, wherein

[0207] Z is an aryl group, preferably phenyl, and each of the aryl groups is further optionally substituted with one or more fluorine groups;

[0208] R1 is H;

[0209] R2 is selected from

[0210] Heteroaryl (C1-C4)alkyl-, which are (pyridyl)methyl, (pyridazinyl)methyl, ( (diazolyl)ethyl, (pyrimidinyl)ethyl,

[0211] Each of the heteroarylalkyl groups is further optionally substituted with one or more groups selected from methyl and trifluoromethyl;

[0212] J is H;

[0213] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 7 below and their pharmaceutically acceptable salts.

[0214] Table 7: List of preferred compounds having formula (Ic)

[0215]

[0216]

[0217] Compounds of formula (I), including all the compounds listed above, can typically be prepared using generally known methods, following the procedures outlined in the scheme shown below.

[0218] Option 1

[0219]

[0220] In one embodiment of the invention, compound (Ia) can be prepared from intermediate (II) according to scheme 1.

[0221] Intermediate (III) can be prepared from intermediate (IIa) in the presence of a suitable amine (reagent 1) by a deoxyamination reaction mediated by a reagent such as PyBOP or a similar reagent, or by reacting with a suitable amine (reagent 1) from intermediate (IIb).

[0222] Compound (Ia) can be prepared from intermediate (III) by metal-catalyzed crosslinking reaction with a suitable reagent (reagent 2), such as an organoboron reagent, such as Stille or Suzuki or similar reaction.

[0223] In another embodiment of the invention, intermediate (IV) can be prepared from intermediate (IIa) by a metal-catalyzed crosslinking reaction with a suitable reagent (reagent 2) such as an organoboron reagent, such as Stille or Suzuki or a similar reaction.

[0224] Compound (Ia) can be prepared from intermediate (IV) by deoxyamination mediated by a reagent such as PyBOP or similar in the presence of a suitable amine (reagent 1).

[0225] Intermediate (IVa) can be prepared from intermediate (IV) using a suitable chlorinating agent such as, for example, phosphoryl(V) chloride or thionyl chloride.

[0226] Compound (Ia) can be prepared from intermediate (IVa) by amination with a suitable amine (reagent 1) in the presence of a base such as, for example, DIPEA.

[0227] Option 2

[0228]

[0229] In another embodiment of the invention, compound (Ia) can be prepared from intermediate (V) according to scheme 2.

[0230] Intermediate (VI) can be prepared from intermediate (V) by amination reaction with a suitable amine (reagent 1) in the presence of a base such as, for example, DIPEA.

[0231] Intermediate (VII) can be prepared from intermediate (VI) by amination reaction with a suitable amine (reagent 4) in the presence of a base such as, for example, DIPEA.

[0232] Compound (Ia) can be prepared from intermediate (VII) by metal-catalyzed crosslinking reaction with a suitable reagent (reagent 2), such as an organoboron reagent, such as Stille or Suzuki or similar reaction.

[0233] Option 3

[0234]

[0235] In one embodiment of the invention, compound (Ib) can be prepared from intermediate (VIII) according to scheme 3.

[0236] Intermediate (IX) can be prepared from intermediate (VIII) by metal-catalyzed crosslinking reaction with a suitable reagent (reagent 2), such as an organoboron reagent, such as Stille or Suzuki or similar reaction.

[0237] Compound (Ib) can be prepared from intermediate (IX) by deoxyamination mediated by a reagent such as PyBOP or similar in the presence of a suitable amine (reagent 1).

[0238] In another embodiment of the invention, intermediate (X) can be prepared from intermediate (VIII) by a deoxyamination reaction mediated by a reagent such as PyBOP or the like in the presence of a suitable amine (reagent 1).

[0239] Compound (Ib) can be prepared from intermediate (X) by metal-catalyzed crosslinking reactions with suitable reagents (reagent 2), such as organoboron reagents, such as Stille or Suzuki or similar reactions.

[0240] Option 4

[0241]

[0242] In one embodiment of the invention, compound (Ib) can be prepared from intermediate (XI) according to scheme 4.

[0243] Intermediate (XII) can be prepared from intermediate (XI) by a deoxyamination reaction mediated by a reagent such as PyBOP or the like in the presence of a suitable amine (reagent 1).

[0244] Compound (Ib) can be prepared from intermediate (XII) by metal-catalyzed crosslinking reactions with suitable reagents (reagent 2), such as organoboron reagents, such as Stille or Suzuki or similar reactions.

[0245] Option 5

[0246]

[0247] In one embodiment of the invention, compound (Ic) can be prepared from intermediate (XIII) according to scheme 5.

[0248] Intermediate (XIV) can be prepared from intermediate (XIII) by means of a ring-forming reaction mediated by a suitable reagent, such as triethyl orthoformate.

[0249] Intermediate (XV) can be prepared from intermediate (XIV) by metal-catalyzed crosslinking reaction with a suitable reagent (reagent 2), such as an organoboron reagent, such as Stille or Suzuki or similar reaction.

[0250] Intermediate (XVI) can be prepared from intermediate (XV) by a deoxyhalogenation reaction mediated by a reagent such as thionyl chloride or the like.

[0251] Compound (Ic) can be prepared from intermediate (XVI) by amination reaction with a suitable amine R1 in the presence of a base such as, for example, DIPEA.

[0252] In one specific aspect, the present invention relates to compounds of formula (IIIa).

[0253]

[0254]

[0255] Where X is N or CH.

[0256] R7 is OH and / or Cl;

[0257] R8 is halogenated.

[0258] In another aspect, the present invention relates to the use of compounds of formula (IIIa) as described above as intermediates in the preparation of compounds of formula (I).

[0259] It has been surprisingly discovered that the compounds of the present invention effectively inhibit the P2X3 receptor, and that the compounds can be used to treat respiratory diseases.

[0260] In one embodiment, it has been surprisingly found that the representative compound of formula (I) of the present invention effectively and selectively inhibits the P2X3 receptor, and the compound can be used to treat respiratory diseases while avoiding adverse effects such as loss of taste response.

[0261] The compound of formula (I) is a selective P2X3 antagonist, wherein the selectivity of the selective P2X3 antagonist for antagonizing the P2X3 homomeric receptor is specific to the P2X3 homomeric receptor. 2 / 3 It has at least 10 times the antagonistic effect of heteromer receptors.

[0262] In a preferred embodiment, the selectivity of the selective P2X3 antagonist for antagonizing the P2X3 homopolymer receptor is specific to the P2X3 homopolymer receptor. 2 / 3 It has at least 30 times the antagonistic effect of heteromer receptors.

[0263] In another preferred embodiment, the selectivity of the selective P2X3 antagonist to the P2X3 homopolymer receptor is selective for P2X3 homopolymer receptor antagonism. 2 / 3 It has at least 50 times the antagonistic effect of heteromer receptors.

[0264] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more other active ingredients, mixed with one or more pharmaceutically acceptable carriers or excipients.

[0265] In one aspect, the present invention relates to compounds of formula (I) according to the invention for use as pharmaceuticals.

[0266] In another aspect, the present invention relates to the use of compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof in the preparation of pharmaceuticals for treating disorders related to the P2X3 receptor mechanism, preferably for treating respiratory diseases.

[0267] Preferably, the present invention relates to compounds of formula (I) for the prevention and / or treatment of respiratory diseases, particularly 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.

[0268] More preferably, the present invention relates to compounds of formula (I) for the prevention and / or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0269] The present invention also relates to a method for preventing and / or treating disorders related to the P2X3 receptor mechanism, the method comprising administering a therapeutically effective amount of the compound of the present invention to a patient requiring such treatment.

[0270] In another embodiment, the disorder that can be treated by the compounds of the present invention is selected from 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.

[0271] In another preferred embodiment, the barrier is selected from cough and chronic cough.

[0272] The treatment method of the present invention comprises administering to a patient in need a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, a “safe and effective amount” for a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of compound sufficient to treat the patient’s condition, but low enough to avoid serious side effects, though this can routinely be determined by a skilled technician. A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or according to a dosing regimen in which several doses are administered at varying time intervals over a given period. A typical daily dose may vary depending on the specific route of administration chosen.

[0273] The present invention also provides pharmaceutical compositions of compounds of formula (I) mixed with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, 1980, Mack Pub., NY, USA.

[0274] The compounds and pharmaceutical compositions thereof of the present invention can be administered according to the patient's needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternalally, and by infusion), and by inhalation.

[0275] Preferably, the compounds of the invention are administered orally and by inhalation.

[0276] Various solid oral dosage forms can be used to administer the compounds of the present invention, including tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, and starch), and known excipients, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavorings, lubricants, etc. Time-limited release capsules, tablets, and gels are also advantageous for administering the compounds of the present invention.

[0277] Preferably, the compound of the present invention is administered in tablet form.

[0278] Various liquid oral dosage forms can also be used to administer the compounds of the present invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and reagents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention can be injected, for example, intravenously as an isotonic sterile solution.

[0279] For the treatment of respiratory diseases, the compounds according to the invention are preferably administered by inhalation.

[0280] Inhalable preparations include inhalable powders, metered-dose aerosols containing propellants, or inhalable formulations without propellants.

[0281] For administration as a dry powder, single- or multi-dose inhalers known according to the prior art can be used. In this case, the powder can be filled in gelatin, plastic, or other capsules, cartridges, blister packs, or in a reservoir.

[0282] Chemically inert diluents or carriers to the compounds of the present invention, such as lactose or any other additives suitable for improving the respirable fraction, may be added to the powdered compounds of the present invention.

[0283] Inhaled aerosols containing a propellant gas (such as hydrofluorocarbons) may contain the compounds of the present invention in solution or dispersion form. Propellant-driven formulations may also contain other components, such as cosolvents, stabilizers, or optional other excipients.

[0284] Propellant-free inhalable formulations containing the compounds 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 jet or ultrasonic atomizers known in the art or by soft atomizers.

[0285] Preferably, the compound of the present invention is administered orally.

[0286] The compounds of the present invention can be used as the sole active agent or in combination with other pharmaceutical active ingredients.

[0287] The dosage of the compounds of the present invention depends on a variety of factors, including the specific disease to be treated, the severity of symptoms, and the route of administration.

[0288] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound according to formula (I) of the present invention, the device being in the form of a single-dose or multiple-dose dry powder inhaler or a metered-dose inhaler.

[0289] The following examples illustrate various aspects of the invention described in this application and are not intended to limit the invention in any way. The following examples illustrate the invention.

[0290] The embodiments and experiments described herein are used to illustrate the present invention, and the present invention is not limited to the given embodiments.

[0291] Preparation of intermediates and examples

[0292] Use Dotmatics software to generate chemical names. In some cases, the generally accepted names of commercially available reagents are used instead of the names generated by Dotmatics software.

[0293] All reagents whose synthesis is not described in the experimental section are commercially available, or are known compounds, or can be formed from known compounds by those skilled in the art using known methods.

[0294] (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethylamine HCl and (R)-1-(6-methylpyridazin-3-yl)ethane-1-amine HCl were prepared according to the procedure described in WO2016 / 091776.

[0295] Abbreviation - Meaning

[0296] Et2O: Diethyl ether;

[0297] Et3N: Triethylamine;

[0298] TEA: Triethylamine;

[0299] DCC:N,N'-Dicyclohexylcarbodiimide;

[0300] PyBOP: (benzotriazol-1-yloxy)tripyrrolidino phosphorus Hexafluorophosphate;

[0301] DMF: Dimethylformamide;

[0302] EtOAc: Ethyl acetate;

[0303] RT: Room temperature;

[0304] THF: Tetrahydrofuran;

[0305] DCM: Dichloromethane;

[0306] MeOH: Methanol;

[0307] EtOH: Ethanol;

[0308] TFA: Trifluoroacetic acid;

[0309] LC-MS: Liquid Chromatography / Mass Spectrometry;

[0310] HPLC: High-performance liquid chromatography;

[0311] MPLC: Medium-pressure liquid chromatography;

[0312] SFC: Supercritical Fluid Chromatography;

[0313] dppf:1,1'-bis(diphenylphosphino)ferrocene;

[0314] DIEA or DIPEA: N,N-diisopropylethylamine;

[0315] MeCN: Acetonitrile;

[0316] MTBE: tert-butyl methyl ether;

[0317] TBDMSCl: tert-butyl(chloro)dimethylsilane;

[0318] DMSO: Dimethyl sulfoxide;

[0319] Boc2O: ditert-butyl dicarbonate;

[0320] UPLC: Ultra-high performance liquid chromatography.

[0321] General experimental details and methods

[0322] Analytical methods

[0323] Liquid Chromatography-Mass Spectrometry

[0324] Method 1

[0325] UPLC-MS was performed using a Waters HSS C18 column (1.8 μm, 100 × 2.1 mm) on a Waters Acquity I-Class mass spectrometer coupled to a Waters SQD2 single quadrupole mass spectrometer with a Waters diode array detector. The column was initially held in 5% acetonitrile / water (containing 0.1% formic acid in each mobile phase) for 1.2 min, followed by a linear gradient of 5–100% over 3.5 min, and then held at 100% for 1.5 min (F = 0.5 mL / min).

[0326] Method 2

[0327] UPLC-MS was performed using a Waters BEH Shield RP18 column (1.7 μm, 100 × 2.1 mm) coupled to a Waters SQD2 single quadrupole mass spectrometer on a Waters Acquity I-Class with a Waters diode array detector. The column was initially held in 5% acetonitrile / water (containing 10 mM ammonium bicarbonate in each mobile phase) for 1.2 min, followed by a linear gradient of 5–100% over 3.5 min, and then held at 100% for 1.5 min (F = 0.5 mL / min).

[0328] Method 3

[0329] UPLC-MS was performed on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7µm 100x 2.1mm (+guard column) maintained in a temporary column. The column was initially held in 5% acetonitrile / water (containing 10mM ammonium bicarbonate in each mobile phase) for 0.4 min, followed by a linear gradient of 5-95% over 6.4 min, and then held at 95% for 1.2 min (F = 0.4 mL / min).

[0330] Method 4

[0331] UPLC-MS was performed on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7µm 100x 2.1mm (+guard column) maintained in a temporary column. The column was initially held for 0.4 min in 5% acetonitrile (far UV grade) containing 0.1% (v / v) formic acid / water (high purity, via PureLabOption unit) containing 0.1% formic acid, followed by a linear gradient of 5-95% over 6.4 min, and then held at 95% for 1.2 min (F = 0.4 mL / min).

[0332] Method 4.1

[0333] An Acquity UPLC-QDa mass spectrometer with a C18-reversed-phase column (50×2.1mm Acquity CSH, with a particle size of 1.7μm) was maintained at 40°C. The eluents were A: 95 / 5 water / acetonitrile + 0.05% formic acid; B: 95 / 5 acetonitrile / water + 0.05% formic acid.

[0334] gradient:

[0335] Time [min] Flow rate [ml / min] Mobile phase A [%) Mobile phase B [%] 0.0 1 99.0 1.0 1.50 1 0.1 99.9 1.90 1 01 99.9 2.00 1 99.0 1.0

[0336] Detection - MS, UV PDA

[0337] MS ionization method - electro-jet (positive / negative ions).

[0338] Method 4.2

[0339] An Acquity UPLC-QDa mass spectrometer with a C18-reversed-phase column (50×2.1mm Acquity BEH, with a particle size of 1.7μm) was maintained at 40℃. The eluents were A: 95 / 5 water / acetonitrile + 0.05% concentrated ammonia; B: 95 / 5 acetonitrile / water + 0.05% concentrated ammonia.

[0340] gradient:

[0341] Time [min] Flow rate [ml / min] Mobile phase A [%) Mobile phase B [%] 0.0 1 99.0 1.0 1.50 1 0.1 99.9 1.90 1 0.1 99.9 2.00 1 99.0 1.0

[0342] Detection - MS, UV PDA

[0343] MS ionization method - electroejection (positive / negative ions)

[0344] NMR

[0345] Unless otherwise specified, use the solvent at approximately room temperature using a Bruker or Varian instrument running at 400 MHz. 1 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data are consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million, using conventional abbreviations for specifying major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet; dt, doubletuplet; m, multiplet; br, broad peak.

[0346] Preparative reversed-phase HPLC conditions

[0347] Preparative HPLC purification was performed using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / Vis detector, 2767 liquid processor) or an equivalent HPLC system such as the Gilson Trilution UV-guided system, via reversed-phase HPLC. The Waters 2767 liquid processor served as both an autosampler and fraction collector. 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, 5 μm columns. An appropriate focusing gradient was selected based on the acetonitrile and methanol solvent system, 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 controlled by monitoring at 210–400 nm using Waters Fractionlynx software, with a collection threshold triggered at 260 nm. The presence of the target molecular ion was observed under API conditions when using Fractionlynx. The collected fractions were analyzed by LCMS (Waters Acquity system with Waters SQD).

[0348] Chiral supercritical fluid chromatography (SFC) separation scheme

[0349] Diastereomeric separation of compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / Vis detector, 2767 liquid processor with stacked injection module). The Waters 2767 liquid processor served as both an autosampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol, or isopropanol solvent systems under unmodified or alkaline conditions. The standard SFC method used was modifier, CO2, 100 mL / min, 120 bar back pressure, and a column temperature of 40 °C. The modifier used under alkaline conditions was diethylamine (0.1% V / V). The modifier used under acidic conditions was formic acid (0.1% V / V) or trifluoroacetic acid (0.1% V / V). SFC purification was controlled by monitoring at 210–400 nm using Waters Fractionlynx software, with the collection threshold typically triggered at 260 nm. The collected fractions were analyzed using an SFC (Waters / Thar SFC system with Waters SQD). The fraction containing the desired product was concentrated by vacuum centrifugation.

[0350] Supercritical fluid chromatography-mass spectrometry analysis conditions

[0351] Method 5

[0352] SFC-MS was performed using a Lux Cellulose-3 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 15% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0353] Method 6

[0354] SFC-MS was performed using a Lux Cellulose-3 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 20% ​​methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0355] Method 7

[0356] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 55% ethanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and a column temperature of 40 °C.

[0357] Method 8

[0358] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic running at 5 mL / min of 20% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and a column temperature of 40 °C.

[0359] Method 9

[0360] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 30% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0361] Method 10

[0362] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 50% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0363] Method 11

[0364] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 25% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0365] Method 12

[0366] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 15% ethanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0367] Method 13

[0368] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 25% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0369] Method 14

[0370] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 35% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0371] Method 15

[0372] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 55% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0373] Method 16

[0374] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 15% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0375] Method 17

[0376] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 20% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and a column temperature of 40 °C.

[0377] Method 18

[0378] SFC-MS was performed using a YMC Cellulose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 15% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0379] Method 19

[0380] SFC-MS was performed using a YMC Cellulose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 15% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0381] Method 20

[0382] SFC-MS was performed using a YMC Cellulose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 25% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0383] Method 21

[0384] SFC-MS was performed using a YMC Cellulose-SC column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 55% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0385] Method 22

[0386] SFC-MS was performed using a Lux Cellulose-3 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 10% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0387] Method 23

[0388] SFC-MS was performed using a Lux Cellulose-3 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 30% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0389] Method 24

[0390] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 20% ​​methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0391] Method 25

[0392] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 40% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0393] Method 26

[0394] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 55% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0395] Method 27

[0396] SFC-MS was performed using a Lux Cellulose-4 column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 55% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and a column temperature of 40 °C.

[0397] Method 28

[0398] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 20% ​​ethanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and a column temperature of 40 °C.

[0399] Method 29

[0400] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 25% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0401] Method 30

[0402] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min of 55% methanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0403] Method 31

[0404] SFC-MS was performed using a YMC Amylose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 30% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0405] Method 32

[0406] SFC-MS was performed using a YMC Cellulose-C column on a Waters / Thar SFC system with Waters SQD, with isocratic operation at 5 mL / min using 40% isopropanol / CO2 (containing 0.1% diethylamine), 120 bar back pressure, and 40 °C column temperature.

[0407] Preparation of intermediates and examples

[0408] Intermediate 1

[0409] 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one

[0410]

[0411] A mixture of 2-amino-5-bromonicotinic acid (35 g, 0.16 mol) and formamide (56 mL, 1.41 mol) was heated to 140 °C and maintained for 20 hours. The mixture was cooled to 40 °C and water (100 mL) was added. The mixture was stirred for 30 minutes, and then additional water (300 mL) was added. The reaction mixture was filtered, and the solid was washed with water (3 × 100 mL), a solution of 10% methanol in diethyl ether (3 × 100 mL), and diethyl ether (3 × 100 mL) to give the title compound (33.0 g, 90% yield) as a light brown solid.

[0412] 1 ¹H NMR (400MHz, DMSO): δ 12.78–12.77 (m, 1H), 9.09 (d, J = 2.5Hz, 1H), 8.67 (d, J = 2.5Hz, 1H), 8.41 (s, 1H). LCMS (Method 4): [MH+] = 226 at 2.38 min.

[0413] Intermediate 2

[0414] 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one

[0415]

[0416] Nitrogen gas was used to bubble 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 1) (1.0 g, 4.42 mmol), 4-fluorophenylboronic acid (929 mg, 6.64 mmol), and cesium carbonate (4.32 g, 13.27 mmol) in a mixture of N,N-dimethylformamide (10 mL) and water (2 mL) for 5 min, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (664 mg, 0.57 mmol). The resulting mixture was heated to 95 °C and maintained for 16 h. After returning to room temperature, the reactants were diluted with water (20 mL), filtered, and the solid was washed with diethyl ether to give the title compound (965 mg, 90%) as a beige solid.

[0417] LCMS (Method 4): [MH+] = 242 at 2.90 min.

[0418] The following compounds were synthesized according to the procedure described in the preparation of 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one:

[0419]

[0420] Example 1

[0421] 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-] Diazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine

[0422]

[0423] Add (benzotriazol-1-yloxy)tripyrrolidinephosphine sequentially to a solution of 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 2) (516 mg, 2.14 mmol) in N,N-dimethylformamide (15 mL). Hexafluorophosphate (1.17 g, 2.25 mmol) and diisopropylethylamine (1.7 mL, 9.63 mmol). The resulting mixture was heated to 45 °C and held for 45 minutes, then 1-(3-methyl-1,2,4-) was added. Diazol-5-yl)ethane-1-amine hydrochloride (600 mg, 3.0 mmol) was heated at 45 °C for 16 hours. After returning to room temperature, the mixture was diluted with ethyl acetate (25 mL) and water (70 mL). The organic phase was washed with brine (2 × 20 mL), passed through a hydrophobic glass frit, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (190 mg, 25%) as a white solid.

[0424] 1¹H NMR (400MHz, DMSO): δ 9.45 (d, J = 2.3Hz, 1H), 9.26–9.21 (m, 2H), 8.69 (s, 1H), 8.04–7.99 (m, 2H), 7.49 (dd, J = 8.8, 8.8Hz, 2H), 5.88 (d, J = 6.8Hz, 1H), 2.38 (s, 3H), 1.81 (d, J = 7.1Hz, 3H). LCMS (Method 3): [MH+] = 351 at 3.68 min.

[0425] Intermediate 20

[0426] 6-(5-methylthiazolyl)pyrido[2,3-d]pyrimidin-4(3H)-one

[0427]

[0428] Step 1: Preparation of 6-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)-pyrido[2,3-d]pyrimidine

[0429]

[0430] 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (7.0 g, 30.97 mmol) was dissolved in N,N-dimethylformamide (260 mL), and the reaction mixture was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 1.49 g, 37.16 mmol) was added fractionally, and the reaction mixture was stirred for 30 min. Then (2-chloromethoxyethyl)trimethylsilane (8.2 mL, 46.45 mmol) was added dropwise. The reaction mixture was then stirred at 0 °C for 1 h and then warmed to room temperature. The reaction mixture was quenched with water (50 mL) and partitioned with ethyl acetate (50 mL). The phases were separated, and the aqueous layer was washed with ethyl acetate (3 × 50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel, eluting with a solution of 0-70% ethyl acetate in dichloromethane to give the title compound (6.0 g, 54%) as a white solid.

[0431] 1 H NMR (400MHz, CDCl3): δ9.01 (d, J = 2.4Hz, 1H), 8.74 (d, J = 2.4Hz, 1H), 8.40 (s, 1H), 5.52 (s, 2H), 3.66-3.62 (m, 2H), 0.98-0.95 (m, 2H), 0.02 (s, 9H).

[0432] Step 2: Preparation of 5-methyl-2-(4-((2-(trimethylsilyl)ethoxy)-methoxy)pyrido[2,3-d]pyrimidin-6-yl)thiazole

[0433]

[0434] Nitrogen gas was used in the reaction of 6-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[2,3-d]pyrimidine (3500 mg, 9.82 mmol), bis(pinacolato)diboron (2993 mg, 11.79 mmol), a complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane (401 mg, 0.49 mmol), and potassium acetate (1928 mg, 19.65 mmol) in 1,4-di... Bubbling was performed for 5 minutes in a suspension of 80 mL of alkylene. The reaction mixture was heated to 100 °C and maintained for 16 hours. The reaction mixture was cooled to room temperature. Water (16 mL), 2-bromo-5-methyl-1,3-thiazole (1836 mg, 10.3 mmol), cesium carbonate (6401 mg, 19.7 mmol), and another aliquot of the complex of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride with dichloromethane (22 mg, 0.027 mmol) were added to the resulting suspension. The reaction mixture was heated to 100 °C and maintained for another 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and passed through a hydrophobic glass frit. The solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel, eluting with a solution of 30–50% ethyl acetate in dichloromethane. The resulting residue was ground together with diethyl ether to give the title compound (2400 mg, 65%) as a pale yellow solid.

[0435] LCMS (Method 4): [MH+] = 375 at 5.09 min.

[0436] Step 3: Preparation of 6-(5-methylthiazolyl)pyrido[2,3-d]pyrimidin-4(3H)-one

[0437]

[0438] 5-Methyl-2-(4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[2,3-d]pyrimidin-6-yl)thiazole (1000 mg, 2.67 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum, and the residue was quenched with a saturated solution of sodium bicarbonate and water. The solid was filtered and dried under reduced pressure to give the title compound (458 mg, 70%) as a yellow solid.

[0439] LCMS (Method 4): [MH+] = 245 at 2.73 min.

[0440] The following compounds were synthesized according to the procedure described in the preparation of 6-(5-methylthiazo-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one:

[0441]

[0442]

[0443] Example 49

[0444] 6-(5-methylthiazolyl-2-yl)-N-[[3-(trifluoromethyl)-1,2,4- [diazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine

[0445]

[0446] 6-(5-methylthiazo-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (60 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.23 mmol) were suspended in toluene (2.5 mL). The reaction mixture was heated at 95 °C and phosphoryl chloride (0.027 mL, 0.30 mmol) was added. The reaction mixture was heated at 95 °C for 2 hours and then cooled to room temperature. The solvent was removed under vacuum. [3-(trifluoromethyl)-1,2,4- [Diazol-5-yl]methylamine hydrochloride (75 mg, 0.37 mmol), potassium carbonate (102 mg, 0.74 mmol), and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reactants were diluted with ethyl acetate and passed through... Filter the mixture through a pad. Remove the solvent under vacuum. Purify the resulting residue by preparative HPLC to give the title compound (3.1 mg, 3%) as a pale yellow solid.

[0447] 1¹H NMR (400MHz, DMSO): δ 9.90–9.86 (m, 1H), 9.60 (d, J = 2.3 Hz, 1H), 9.30 (d, J = 2.3 Hz, 1H), 8.69 (s, 1H), 7.83–7.81 (m, 1H), 5.25 (d, J = 3.7 Hz, 2H), 2.63 (d, J = 1.1 Hz, 3H). LCMS (Method 4): [MH+] = 394 at 3.69 min.

[0448] According to the information regarding 6-(5-methylthiazol-2-yl)-N-[[3-(trifluoromethyl)-1,2,4- The preparation of diazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine follows the described procedure to synthesize the following compounds:

[0449]

[0450]

[0451] Intermediate 24

[0452] 6-(1-((6-(4-fluorophenyl)pyridino[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one

[0453]

[0454] Step 1: Preparation of 4-chloro-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine

[0455]

[0456] Phosphoryl chloride (0.5 mL, 5.39 mmol) was added under nitrogen to a stirred suspension of 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (1 g, 4.15 mmol) and N,N-diisopropylethylamine (3.6 mL, 20.7 mmol) in anhydrous toluene (20 mL). The mixture was heated to 90 °C and held for 2 hours, after which LC-MS analysis indicated conversion to the desired target. The solvent was removed under vacuum, and the resulting residue was partitioned between DCM (40 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The layers were thoroughly mixed before separation, and the aqueous phase was redissolved with DCM (20 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (10 mL), then washed with water (10 mL), and dried by passing through a phase separation glass frit. The solvent was removed under vacuum to obtain a dark brown semi-solid, which was immediately used in the next step without further purification (1.6 g, >100%).

[0457] Step 2: Preparation of 6-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one

[0458]

[0459] 4-Chloro-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine (150 mg, 0.58 mmol), 6-(1-aminoethyl)pyridin-2(1H)-one·HBr (152 mg, 0.69 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.31 mmol) were stirred in N,N-dimethylformamide (4 mL) at 40 °C for 4 days. The yellow precipitate was filtered off and purified by preparative HPLC to give the title compound (61 mg, 29%) as a colorless solid.

[0460] 1 H NMR (400MHz, DMSO): δ11.76-11.75(m,1H),9.42(d,J=2.5Hz,1H),9.22(d,J=2.5Hz,1H),8.83(d,J=6.8Hz,1H),8.65(s,1H),8.03(ddd,J=3.2,5 .4,12.0Hz,2H),7.50(dd,J=8.8,8.8Hz,2H),7.40(dd,J=8.0,8.0Hz,1H),6.28-6.21(m,2H),5.38(dd,J=6.9,6.9Hz,1H),1.65(d,J=7.1Hz,3H). LCMS (Method 4): [MH+] = 362 at 2.85 min.

[0461] The following compounds were synthesized using a suitable amine reagent, following the same procedure described in the preparation of 6-(1-((6-(4-fluorophenyl)pyridino[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one:

[0462]

[0463]

[0464]

[0465]

[0466]

[0467] Example 2

[0468] (R)-5-(1-((6-(4-fluorophenyl)pyridino[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine-1-oxide

[0469]

[0470] 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 2) (23.5 g, 97.4 mmol, 1 equivalent) was suspended in SOCl2 (240 mL), and then DMF (2.5 mL) was added dropwise. The reaction mixture was heated to reflux until a clear solution was formed. The reaction was then stopped and the volatiles were removed under reduced pressure. The residue was impregnated with EtOAc, then filtered and dried to give 4-chloro-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin (23.6 g, 91.9 mmol, 94% yield).

[0471] DIPEA (0.3 mL, 1.722 mmol) was added to a mixture of 4-chloro-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine (100 mg, 0.385 mmol) and (R)-5-(1-aminoethyl)-2-(trifluoromethyl)pyridine 1-oxide hydrochloride (112 mg, 0.462 mmol) in DMF (volume: 2 mL). Stirring was continued at 80 °C for 16 h. The reaction mixture was diluted with AcOEt, washed with a semi-saturated aqueous NaCl solution, and then washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by DP chromatography (Biotage Isolera, 28g NH column, gradient elution with 0-60% AcOEt in dichloromethane) followed by RP chromatography (Biotage Isolera, 30g C18 column, gradient elution with 0-35% B in A. A: water / acetonitrile 95:5 + 0.05% HCOOH, B: acetonitrile / water 95:5 + 0.05% HCOOH) to produce (R)-5-(1-((6-(4-fluorophenyl)pyridino[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide as a grayish-white powder (122 mg, 0.284 mmol, 73.8% yield).

[0472] LCMS (Method 4.1): 0.70 min, 430.1 [M+H]+.

[0473] ¹H NMR (400MHz, DMSO-d6) δppm 9.36 (d, J = 2.19Hz, 1H) 9.14 (d, J = 2.19Hz, 1H) 8.88 (d, J = 6.80Hz, 1H) 8.61 (s, 1H) 8.59 (s, 1H) 7.97 (dd, J = 8.47, 5.38Hz, 2H) 7.91 (d, J = 8.33Hz, 1H) 7.58 (d, J = 8.33Hz, 1H) 7.44 (t, J = 8.77Hz, 2H) 5.55 (quintet, J = 6.96Hz, 1H) 1.66 (d, J = 7.02Hz, 3H).

[0474] The following embodiments were synthesized through improvements to the same procedure.

[0475]

[0476]

[0477]

[0478] Intermediate 3 - Program A

[0479] 6-Bromo-N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[0480]

[0481] To 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 1) (1.0 g, 4.42 mmol) and 1-(3-methyl-1,2,4- The mixture of diazol-5-yl)ethane-1-amine hydrochloride (996 mg, 4.98 mmol) in N,N-diisopropylethylamine (3.9 mL, 22.12 mmol) and (benzotriazol-1-yloxy)tripyrrolidino phosphoric acid was added to the mixture in N,N-dimethylformamide (25 mL). Hexafluorophosphate (2.76 g, 5.31 mmol) was added, and the mixture was heated to 40 °C and maintained for 5 hours, followed by heating at room temperature for 2 days. The reaction mixture was filtered, and the solid was washed with ethyl acetate (20 mL). The filtrate was washed with water (100 mL), and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (50 mL), passed through a hydrophobic glass frit, and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel, eluting with a solution of 0–10% methanol in dichloromethane. The fractions containing the product were combined and ground with diethyl ether to give the title compound as a white solid (766 mg, 46% yield).

[0482] LCMS (Method 3): [MH+] = 335 at 2.94 min.

[0483] Intermediate 4 - Program B

[0484] 6-Bromo-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

[0485]

[0486] 6-Bromo-4-chloropyridino[2,3-d]pyrimidine (1 g, 4.09 mmol), (6-methylpyridin-3-yl)methylamine (0.500 g, 4.09 mmol), and triethylamine (3 ml, 21.52 mmol) were prepared in a 1,4-didioxymetholamine solution. The mixture in alkyl / DMF 5:1 (volume: 12 ml) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (Biotage Isolera, 55 g NH column, gradient elution with 0-100% acetone in heptane) gave 6-bromo-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine (1.21 g, 3.66 mmol, 90% yield) as a pale yellow powder. The expected product was recovered as an insoluble precipitate in the fraction and at the top of the column.

[0487] LCMS (CSH alkaline method 2 min): 0.66 min, m / z 329.8 and 331.7 [M]+ and [M+2]+.

[0488] The following intermediates can be synthesized by reacting a suitable substrate with an amine intermediate, using a modified procedure A or B (see table for specific procedures):

[0489]

[0490]

[0491] Example 6

[0492] N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)-6-(5-methylthiazolyl)pyrido[2,3-d]pyrimidin-4-amine

[0493]

[0494] Nitrogen gas was used to treat 5-methyl-2-(tributyltinyl)thiazole (902 mg, 2.67 mmol) and 6-bromo-N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (intermediate 3) (2.75 mg, 0.82 mmol) was bubbled for 5 min in a solution of N,N-dimethylformamide (12 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (0) (142 mg, 0.123 mmol). The resulting mixture was heated to 95 °C and held for 18 h. After returning to room temperature, the reactants were diluted with water (60 mL) and brine (25 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were passed through Column filtration, washing with water (50 mL), drying over MgSO4, and filtration. Solvent removal under vacuum. Purification of the residue by chromatography on silica gel, eluting with a solution of 0-100% methanol in dichloromethane, yielded the title compound as a grayish-white solid (140 mg, 48% yield).

[0495] LCMS (Method 3): [MH+] = 354 at 3.25 min.

[0496] Using a suitable tinane reagent and starting with the intermediates reported in the table, follow the instructions regarding N-(1-(3-methyl-1,2,4-) The following compounds were synthesized using the same procedure described in the preparation of diazol-5-yl)ethyl)-6-(5-methylthiazolyl)pyrido[2,3-d]pyrimidine-4-amine.

[0497]

[0498]

[0499]

[0500]

[0501] Intermediate 7

[0502] 6-(5-chloropyridin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

[0503]

[0504] Nitrogen gas was bubbled in a solution of 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 1) (832 mg, 3.68 mmol), 5-chloro-2-(tributyltinyl)thiazole (2.0 g, 4.97 mmol) in N,N-dimethylformamide (35 mL) for 5 min. Tetra(triphenylphosphine)palladium(0) (638 mg, 0.552 mmol) was added and the mixture was heated to 95 °C and maintained for 18 h. After returning to room temperature, the reactants were filtered and the solid was washed with N,N-dimethylformamide (50 mL), followed by washing with a solution of 10% methanol in dichloromethane (3 × 25 mL) to give the title compound (470 mg, 49%) as an off-white solid.

[0505] 1 H NMR (400MHz, DMSO): δ12.72-12.72(m,1H),9.70-9.66(m,1H),9.15(s,1H),8.85(s,1H),8.42(s,1H),8.34(d,J=8.6Hz,1H),8.16(d,J=7.3Hz,1H).

[0506] Example 11

[0507] (R)-6-(5-chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[0508]

[0509] To a solution of 6-(5-chloropyridin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 7) (80 mg, 0.31 mmol) in N,N-dimethylformamide (8 mL), (6-methylpyridin-3-yl)methylamine dihydrochloride (69 mg, 0.35 mmol), N,N-diisopropylethylamine (0.27 mL, 1.55 mmol), and (benzotriazol-1-yloxy)tripyrrolidinephosphine were added. Hexafluorophosphate (1.93 mg, 0.37 mmol). The resulting mixture was heated to 60 °C and held for 48 hours. After returning to room temperature, the reactants were diluted with dichloromethane (10 mL) and water (20 mL) and filtered. The solid was washed with water (5 mL) and dichloromethane (10 mL) and the filtrate was separated. The aqueous phase was further extracted with dichloromethane (2 × 15 mL). The organic phases were combined, passed through a hydrophobic glass frit, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (9.5 mg, 7%) as a grayish-white solid.

[0510] 1 ¹H NMR (400MHz, DMSO): δ 9.74 (d, J = 2.0Hz, 1H), 9.55 (d, J = 2.0Hz, 1H), 9.25 (s, 2H), 9.21 (d, J = 6.1Hz, 1H), 8.88 (d, J = 2.0Hz, 1H), 8.67 (s, 1H), 8.32 (d, J = 8.6Hz, 1H), 8.25 (dd, J = 2.3, 8.6Hz, 1H), 5.77–5.71 (m, 1H), 1.81 (d, J = 7.1Hz, 3H). LCMS (Method 4): [MH+] = 432 at 3.71 min.

[0511] The following compounds were synthesized using a suitable amine reagent, following the same procedure described in the preparation of (R)-6-(5-chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine:

[0512]

[0513] Example 13

[0514] (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

[0515]

[0516] Nitrogen gas was used in the following atmospheres: (R)-6-bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (100 mg, 0.251 mmol), potassium carbonate (104 mg, 0.752 mmol), 4-fluorophenylboronic acid (39 mg, 0.276 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (18 mg, 0.0251 mmol), and 1,4-di... The mixture was bubbled for 10 min in a mixture of alkane (2 mL) and water (0.5 mL). The reaction mixture was heated to 110 °C in a microwave reactor and held for 20 min. After returning to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography, eluting with a solution of 0–20% methanol in dichloromethane, followed by preparative HPLC to give the title compound (37 mg, 35%) as a grayish-white solid.

[0517] 1 ¹H NMR (400MHz, CDCl₃): δ 9.21 (d, J = 2.4Hz, 1H), 8.56 (d, J = 2.3Hz, 1H), 7.51 (d, J = 1.0Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.36 (d, J = 8.7Hz, 1H), 5.04 (d, J = 4.8Hz, 2H), 4.03–4.03 (m, 2H), 3.97–3.96 (m, 2H), 3.69 (dd, J = 5.1, 5.1Hz, 2H), 3.53 (dd, J = 5.1, 5.1Hz, 2H), 2.75 (s, 3H), 2.54 (s, 3H), 2.16 (s, 3H). LCMS (Method 3): [MH⁺] = 476.0 at 3.06 min.

[0518] Compound 18 was obtained as a byproduct in the preparation of Example 17.

[0519] The following intermediates can be synthesized by improving the same procedure, starting with a suitable intermediate:

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] Example 19

[0526] N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine

[0527]

[0528] DIPEA (0.15 mL, 0.861 mmol) was added to a mixture of 6-bromo-4-chloropyrido[2,3-d]pyrimidine (100 mg, 0.409 mmol) and (3,5-difluoropyridin-2-yl)methylamine hydrochloride (73.9 mg, 0.409 mmol) in DMF (volume: 2 mL). Stirring was continued at 80 °C for 6 h. After the conversion of the starting material to 6-bromo-N-((3,5-difluoropyridin-2-yl)methyl)pyrido[2,3-d]pyrimidine-4-amine was completed, water (1 mL) was added to the reaction mixture, followed by 4-fluorophenylboronic acid (86 mg, 0.614 mmol), potassium phosphate (174 mg, 0.818 mmol), and Pd(dppf)Cl2·CH2Cl2 (33.4 mg, 0.041 mmol). Stirring was continued at 80 °C for 16 h. The mixture was cooled to room temperature, and then formic acid (0.154 mL, 4.09 mmol) was added. Purification was performed by RP chromatography (Biotage Isolera, 30 g C18 column, gradient elution from 100:0 to 30:70 A / B, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH, 15 column volumes) to yield N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine (35.8 mg, 0.097 mmol, 23.83% yield) as a grayish-white powder.

[0529] LCMS: 0.70 min, m / z 367.9 [M+H]+, (Method 4.1):.

[0530] 1H NMR(400MHz,DMSO-d6)δppm 9.29-9.47(m,1H),9.20(t,1H),9.10(d,J=2.41Hz,1H),8.54-8.63(m,1H),8. 38-8.49(m,1H),7.81-8.04(m,3H),7.42(t,J=8.88Hz,2H),4.93-5.03(m,2H).

[0531] The following examples were synthesized using appropriate amines and boric acids or esters, starting from 6-bromo-4-chloropyridinium and [2,3-d]pyrimidine, through a modified version of the same procedure.

[0532]

[0533] Intermediate 8

[0534] 6-Bromopyrido[2,3-d]pyrimidine-2,4-diol

[0535]

[0536] 2-Amino-5-bromo-pyridine-3-carboxylic acid (3 g, 13.82 mmol) was finely pulverized together with urea (4.90 g, 81.59 mmol). The mixture was heated in a sand bath to the evaporation point of urea (280 °C) until it solidified. After cooling, the resulting solid was dissolved in 50 mL of 2N sodium hydroxide and then filtered while hot. 6N HCl solution was added dropwise to the mixture until the pH reached 8. The resulting precipitate was filtered off, washed with cold water, and dried under vacuum to give the title compound (3.0 g, 89.5%).

[0537] LCMS (Method 4): [MH+] = 242.0 at 2.58 min.

[0538] Intermediate 9

[0539] 6-Bromo-2,4-dichloropyrido[2,3-d]pyrimidine

[0540]

[0541] N,N-diisopropylethylamine (1.0 mL, 5.74 mmol) was added to a suspension of 6-bromopyrido[2,3-d]pyrimidine-2,4-diol (intermediate 8) (500 mg, 2.07 mmol) in POCl3 (5 mL, 53.65 mmol). The mixture was heated to 120 °C and maintained for 18 hours. The reaction mixture was poured onto ice, diluted with dichloromethane (15 mL), and stirred at room temperature for 1 hour. The aqueous phase was extracted with dichloromethane (2 × 70 mL). The organic phases were combined, washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound (470 mg, 82%) as a red solid.

[0542] LCMS (Method 4): [MH+] = 278.0 at 4.30 min.

[0543] Intermediate 10

[0544] 1-(4-(6-bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one

[0545]

[0546] Step 1: Preparation of 6-bromo-2-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

[0547]

[0548] N,N-diisopropylethylamine (0.69 mL, 3.98 mmol) was added to a solution of 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (intermediate 9) (370 mg, 1.33 mmol) and 6-methylpyridin-3-yl)methylamine dihydrochloride (312 mg, 1.59 mmol) in tert-butanol (10 mL). The reaction mixture was heated to 40 °C and maintained for 1 hour. The solvent was removed under vacuum, and the residue was used for the next step without further purification.

[0549] LCMS (Method 3): [MH+] = 365.0 at 2.95 min.

[0550] Step 2: Preparation of 1-(4-(6-bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one (intermediate 10)

[0551]

[0552] 6-Bromo-2-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine (485 mg, 1.33 mmol), 1-acetylpiperazine (340 mg, 2.65 mmol), and N,N-diisopropylethylamine (1.2 mL, 6.63 mmol) were dissolved in 1-butanol (10 mL). The reaction mixture was heated to 140 °C and maintained for 1 hour. The reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and washed with water (50 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under vacuum to give the title compound (350 mg, 58%) as a red solid.

[0553] LCMS (Method 3): [MH+] = 457.0 at 2.86 min.

[0554] Examples 21 and 22

[0555] 1-(4-(6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one (Example 21) and 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one (Example 22)

[0556]

[0557] Place 1-(4-(6-bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one (intermediate 10) (50 mg, 0.11 mmol), potassium carbonate (45 mg, 0.33 mmol), 4-fluorophenylboronic acid (17 mg, 0.12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (8 mg, 0.01 mmol) in a microwave-safe bottle. Add 1,4-di... Alkane (2 mL) and water (0.5 mL) were added, and the solution was degassed with nitrogen for 10 minutes. The reaction mixture was heated to 110 °C in a microwave reactor and held for 20 minutes. After returning to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound.

[0558] Example 21 (18 mg, 35%)

[0559] 1 H NMR (400MHz, CDCl3): δ9.00 (d, J = 2.5Hz, 1H), 8.14 (d, J = 2.5Hz, 1H), 7.61-7.56 (m,3H),7.47(d,J=8.5Hz,1H),7.40(d,J=8.5Hz,1H),7.20-7.15(m,2H),5.03( d,J=4.4Hz,2H),4.07(dd,J=3.7,5.5Hz,2H),3.99(dd,J=3.4,5.8Hz,2H),3.71 (dd,J=5.3,5.3Hz,2H),3.55(dd,J=5.2,5.2Hz,2H),2.76(s,3H),2.17(s,3H). LCMS (Method 3): [MH+] = 473.0 at 3.4 min.

[0560] Example 22 (9.0 mg, 21%)

[0561] 1¹H NMR (400MHz, CDCl₃): δ 8.79 (d, J = 3.3Hz, 1H), 8.07 (d, J = 8.1Hz, 1H), 7.47–7.38 (m, 3H), 7.07 (dd, J = 4.8, 8.1Hz, 1H), 5.00 (d, J = 3.8Hz, 2H), 4.05 (t, J = 6.2Hz, 2H), 3.99 (t, J = 4.5Hz, 2H), 3.72–3.68 (m, 2H), 3.54 (dd, J = 4.5, 4.5Hz, 2H), 2.75 (s, 3H), 2.16 (s, 3H). LCMS (Method 3): [MH⁺] = 379.0 at 2.36 min.

[0562] Example 23

[0563] 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylthiazo-2-yl)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one

[0564]

[0565] Nitrogen gas was bubbled in a mixture of 1-(4-(6-bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one (intermediate 10) (50 mg, 0.109 mmol), 5-methyl-2-(tri-n-butyltinyl)thiazole (0.077 mL, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.0164 mmol) in N,N-dimethylformamide (2 mL) for 5 min. The mixture was heated to 80 °C and held for 18 h. After returning to room temperature, the reactants were diluted in methanol (5 mL) and loaded onto an SCX column. The column was washed with methanol, and the filtrate was collected while eluting with a solution of 7 M ammonia in methanol. The solvent was removed under vacuum, and the residue was purified by preparative HPLC to give the title compound (15 mg, 29%) as a grayish-white solid.

[0566] 1¹H NMR (400MHz, CDCl₃): δ 9.21 (d, J = 2.4Hz, 1H), 8.56 (d, J = 2.3Hz, 1H), 7.51 (d, J = 1.0Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.36 (d, J = 8.7Hz, 1H), 5.04 (d, J = 4.8Hz, 2H), 4.03–4.03 (m, 2H), 3.97–3.96 (m, 2H), 3.69 (dd, J = 5.1, 5.1Hz, 2H), 3.53 (dd, J = 5.1, 5.1Hz, 2H), 2.75 (s, 3H), 2.54 (s, 3H), 2.16 (s, 3H). LCMS (Method 3): [MH⁺] = 476.0 at 3.06 min.

[0567] The following compounds were synthesized according to the procedure described in the preparation of 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylthiazo-2-yl)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one:

[0568]

[0569]

[0570] Intermediate 25

[0571] N-[1-(3-Cyclopropyl-1,2,4-] [diazol-5-yl]ethyl]-6-(4-fluorophenyl)pyrido-[2,3-d]pyrimidin-4-amine

[0572]

[0573] 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (200 mg, 0.83 mmol) was suspended in thionyl chloride (1.2 mL, 16.6 mmol) and DMF (0.6 μL, 0.008 mmol). The reaction mixture was heated at 95 °C for 16 hours and cooled to room temperature. The solvent was removed under vacuum. The resulting residue was suspended in a dihydropyrrolidone solution. Add alkyl (5.0 mL), and then add DIPEA (0.72 mL, 4.15 mmol) and [1-(3-cyclopropyl-1,2,4-] to the alkyl group. [Diazol-5-yl]ethyl]amine hydrochloride (236 mg, 1.24 mmol). The reaction mixture was heated at 95 °C for 3 hours and then cooled to room temperature. Water was added, and the resulting solid was filtered and dried under vacuum. The residue was purified by preparative HPLC to give the title compound (257 mg, 82%) as a grayish-white solid, which was a mixture of two enantiomers.

[0574] 1 ¹H NMR (400MHz, DMSO): δ 9.47–9.43 (m, 1H), 9.19–9.16 (m, 2H), 8.68 (s, 1H), 8.05–7.98 (m, 2H), 7.53–7.45 (m, 2H), 5.86–5.79 (m, 1H), 2.20–2.12 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 8.4 Hz, 2H), 0.95–0.87 (m, 2H). LCMS (Method 3): [MH + =377 at 4.09 min.

[0575] According to N-[1-(3-cyclopropyl-1,2,4- The preparation of diazol-5-yl)ethyl]-6-(4-fluorophenyl)-pyrido-[2,3-d]pyrimidin-4-amine follows the described procedure to synthesize the following compounds:

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582] Example 83

[0583] A single enantiomer of 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine 1

[0584] Example 84

[0585] The single enantiomer of 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine 2

[0586]

[0587] 6-(5-fluoropyridin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (200 mg, 0.64 mmol) was suspended in thionyl chloride (1.2 mL, 16.5 mmol) and DMF (0.001 mL). The reaction mixture was heated at 95 °C for 22 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The resulting residue was diluted with saturated NaHCO3 solution and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried and the solvent was removed under vacuum. The residue (145 mg) was dissolved in chloroform (1.0 mL) and 1-(5-methyl-1,3,4-thiadiazol-2-yl)ethane-1-amine (93 mg, 0.65 mmol) was added. The reaction mixture was heated in a sealed test tube at 70 °C under nitrogen for 18 hours. After this time, the resulting mixture was cooled to room temperature. The reaction mixture was diluted with cold water and stirred for 10 minutes. The solid was collected by filtration and then ethyl acetate and water were added. The two phases were separated, and the aqueous phase was extracted with a solution of 5% methanol in ethyl acetate (2 × 50 mL). The combined organic phases were passed through phase separation paper, and the solvent was removed under vacuum. The residue was purified by achiral preparative HPLC followed by chiral preparative SFC to give the title compound as a grayish-white solid.

[0588] Example 83, single enantiomer 1: 24.7 mg, 13%

[0589] 1 H NMR (400MHz, DMSO): δ9.71(d,J=2.4Hz,1H),9.47(d,J=2.4Hz,1H),9.35(d,J=7.4Hz,1H),8.80(d,J=3.0Hz,1H),8 .70(s,1H),8.28(dd,J=4.3,8.8Hz,1H),8.05-7.99(m,1H),6.02-5.97(m,1H),2.67(s,3H),1.82(d,J=7.0Hz,3H). LCMS (Method 4): [MH + =368 at 2.60 min. Chiral analysis (Method 30) at 1.69 min.

[0590] Example 84, single enantiomer 2: 27.3 mg, 14%

[0591] 1H NMR (400MHz, DMSO): δ9.71(d,J=2.4Hz,1H),9.47(d,J=2.5Hz,1H),9.35(d,J=7.5Hz,1H),8.80(d,J=2.9Hz,1H),8 .70(s,1H),8.28(dd,J=4.3,8.8Hz,1H),8.05-7.99(m,1H),6.02-5.97(m,1H),2.67(s,3H),1.82(d,J=7.0Hz,3H). LCMS (Method 4): [MH + =368 at 2.60 min. Chiral analysis (Method 30) at 3.1 min.

[0592] Following the same procedure described for the preparation of a single enantiomer of 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, the following compounds, reported as single isomers, were obtained by chiral preparative SFC purification:

[0593]

[0594]

[0595] Example 91

[0596] 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine

[0597]

[0598] 6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (90 mg, 0.37 mmol) and DIPEA (0.32 mL, 1.87 mmol) were suspended in toluene (3.5 mL). The reaction mixture was heated at 95 °C and phosphoryl chloride (0.042 mL, 0.45 mmol) was added. The reaction mixture was heated at 95 °C for 2 hours and then cooled to room temperature. The solvent was removed under vacuum, and (5-methyl-1,3,4-thiadiazol-2-yl)methylamine hydrochloride (93 mg, 0.56 mmol), DIPEA (0.32 mL, 1.87 mmol), and dimethylamine hydrochloride were added to the resulting residue. Alkane (3.5 mL). The reaction mixture was heated at 95 °C for an additional 5 hours. The reactants were diluted with water and the solid was collected. The precipitate was suspended in DMSO and filtered. The solid was washed with water, then with ethyl acetate and dried under vacuum to give the title compound (31 mg, 24%) as an off-white solid.

[0599] 1 ¹H NMR (400MHz, DMSO): δ 9.62–9.56 (m, 1H), 9.45 (d, J = 1.7 Hz, 1H), 9.09 (s, 1H), 8.77 (s, 1H), 8.02–7.96 (m, 2H), 7.49 (t, J = 8.6 Hz, 2H), 5.19 (d, J = 5.2 Hz, 2H), 2.72 (s, 3H). LCMS (Method 4): [MH + =353 at 2.78 min.

[0600] The following compounds were synthesized according to the procedure described in the preparation of 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine:

[0601]

[0602]

[0603]

[0604] Intermediate 11

[0605] 6-Chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine

[0606]

[0607] 6-chloropyrido[3,4-d]pyrimidin-4(3H)-one (50 mg, 0.27 mmol), (benzotriazol-1-yloxy)tripyrrolidinephosphine Hexafluorophosphate (158 mg, 0.30 mmol) and (6-methylpyridazin-3-yl)methylamine hydrochloride (59 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (1.2 mL, 7 mmol). The reaction mixture was heated at 50 °C for 16 hours. After returning to room temperature, brine (10 mL) was added and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with a solution of 0–20% methanol in dichloromethane to give the title compound (50 mg, 65%).

[0608] LCMS (Method 4): [MH+] = 288.0 at 2.33 min.

[0609] The following compounds were prepared according to the same procedure described in the preparation of 6-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine (intermediate 11):

[0610]

[0611] Example 26

[0612] 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine

[0613]

[0614] Place 6-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine (50 mg, 0.17 mmol), potassium carbonate (96 mg, 0.70 mmol), 4-fluorophenylboronic acid (73 mg, 0.52 mmol), and tetrakis(triphenylphosphine)palladium(O) (30 mg, 0.026 mmol) in a microwave-safe bottle. Add di... Alkane (2 mL) and water (0.5 mL) were added, and the solution was degassed with nitrogen for 10 minutes. The reaction mixture was heated to 110 °C in a microwave reactor and held for 20 minutes. After returning to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with a solution of 0–20% methanol in dichloromethane to give the title compound (9 mg, 15%).

[0615] 1 H NMR (400MHz, DMSO): δ9.57(t,J=5.1Hz,1H),9.32(s,1H),8.97(s,1H),8.71(s,1H),8.39(dd,J=5.6,8.6Hz,2H) ,7.76(d,J=8.6Hz,1H),7.66(d,J=8.6Hz,1H),7.55(dd,J=8.8,8.8Hz,2H),5.21(d,J=5.6Hz,2H),2.74(s,3H). LCMS (Method 4): [MH+] = 347.0 at 3.18 min.

[0616] The following compounds were prepared according to the same procedure described in the preparation of 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine:

[0617]

[0618]

[0619] Example 28

[0620] N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazo-2-yl)pyrido[3,4-d]pyrimidin-4-amine

[0621]

[0622] Nitrogen gas was used to bubble a mixture of 6-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine (intermediate 11) (100 mg, 0.35 mmol), 5-methyl-2-(tributyltinyl)thiazole (271 mg, 0.7 mmol), and potassium carbonate (96 mg, 0.70 mmol) in N,N-dimethylformamide (2 mL) for 5 min. Then, a complex of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride with dichloromethane (57 mg, 0.07 mmol) and Cu(I)I (13 mg, 0.07 mmol) was added. The resulting mixture was heated to 100 °C and held for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate (30 mL), and washed with water (10 mL). The organic phase was passed through The solvent was removed by filtration and under vacuum. The residue was purified by preparative HPLC to give the title compound (9 mg, 7%) as a brown solid.

[0623] 1 ¹H NMR (400MHz, DMSO): δ 9.72 (t, J = 5.5Hz, 1H), 9.13 (s, 1H), 8.99 (s, 1H), 8.59–8.57 (m, 1H), 7.75 (s, 1H), 7.62–7.58 (m, 1H), 7.53–7.49 (m, 1H), 5.05–5.01 (m, 2H), 2.60 (s, 3H), 2.55 (s, 3H). LCMS (Method 4): [MH+] = 350 at 3.01 min.

[0624] The following compounds were prepared according to the same procedure described in the preparation of N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazo-2-yl)pyrido[3,4-d]pyrimidin-4-amine:

[0625]

[0626] Intermediate 13

[0627] 6-Bromo-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine

[0628]

[0629] 6-bromopyrido[3,2-d]pyrimidin-4(3H)-one (150 mg, 0.66 mmol), (benzotriazol-1-yloxy)tripyrrolidinephosphine Hexafluorophosphate (380 mg, 0.73 mmol) and (6-methylpyridazin-3-yl)methylamine hydrochloride (143 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (2.9 mL, 16 mmol). The reaction mixture was heated to 50 °C and maintained for 6 hours. After returning to room temperature, brine (10 mL) was added and the reaction mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with 0–20% methanol in dichloromethane to give the title compound (50 mg, 23%) as a grayish-white solid.

[0630] LCMS (Method 4): [MH+] = 331.0 at 2.92 min.

[0631] The following compounds were prepared according to the same procedure described in the preparation of 6-bromo-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine (intermediate 13):

[0632]

[0633] Example 31

[0634] 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine

[0635]

[0636] Place 6-bromo-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine (intermediate 13) (50 mg, 0.15 mmol), potassium carbonate (63 mg, 0.45 mmol), 4-fluorophenylboronic acid (23 mg, 0.16 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (11 mg, 0.016 mmol) in a microwave-safe bottle. Add 1,4-di... Alkane (2 mL) and water (0.5 mL) were added, and the solution was degassed with nitrogen for 10 minutes. The reaction mixture was heated to 110 °C in a microwave reactor and held for 20 minutes. After returning to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with a solution of 0–20% methanol in dichloromethane to give the title compound (22 mg, 42%) as a grayish-white solid.

[0637] 1 ¹H NMR (400MHz, CDCl₃): δ 8.65 (s, 1H), 8.22 (t, J = 5.9Hz, 1H), 8.19–8.08 (m, 4H), 7.54 (d, J = 8.6Hz, 1H), 7.33 (d, J = 8.6Hz, 1H), 7.23 (t, J = 6.9Hz, 2H), 5.19 (d, J = 6.1Hz, 2H), 2.73 (s, 3H). LCMS (Method 4): [MH⁺] = 347.0 at 2.93 min.

[0638] Example 32

[0639] N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine

[0640]

[0641] Nitrogen gas was bubbled in a mixture of 6-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine (70 mg, 0.21 mmol), 5-methyl-2-(tributyltinyl)pyridine (0.15 mL, 0.42 mmol), and tetrakis(triphenylphosphine)palladium (0) (37 mg, 0.032 mmol) in N,N-dimethylformamide (2 mL) for 5 min. The reaction mixture was heated to 80 °C and held for 18 h. The crude product was cooled to room temperature, diluted in methanol, and loaded onto an SCX column. The column was washed with methanol, and the filtrate was collected while eluting with a solution of 7 M ammonia in methanol. The solvent was removed under vacuum, and the residue was purified by preparative HPLC to give the title compound (19 mg, 26% yield).

[0642] 1¹H NMR (400MHz, CDCl₃): δ 8.84 (d, J = 8.8Hz, 1H), 8.67 (s, 1H), 8.54 (d, J = 1.8Hz, 1H), 8.46 (d, J = 8.0Hz, 1H), 8.27 (dd, J = 5.3, 5.3Hz, 1H), 8.20 (d, J = 8.9Hz, 1H), 7.69 (dd, J = 1.9, 8.2Hz, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.34 (d, J = 8.7Hz, 1H), 5.20 (d, J = 5.9Hz, 2H), 2.74 (s, 3H), 2.43 (s, 3H). LCMS (Method 3): [MH⁺] = 344.2 at 3.34 min.

[0643] The following compounds were synthesized using the same procedure used to prepare N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine:

[0644]

[0645]

[0646] Example 35

[0647] (R)-6-(5-methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine

[0648]

[0649] Potassium carbonate (145 mg, 1.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (86 mg, 0.10 mmol), and cuprous iodide (20 mg) were added to (R)-6-bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine (intermediate 14) (210 mg, 0.53 mmol) in N,N-dimethylformamide (4.0 mL). The mixture was stirred for 10 min and then 3-methyl-5-tributylmethyltinylthiazole (402 mg, 1.05 mmol) was added. The reaction mixture was heated to 100 °C and maintained for 16 h. After returning to room temperature, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were filtered through a hydrophobic glass filter. The solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (7.1 mg, 33%) as a grayish-white solid.

[0650] 1¹H NMR (400MHz, DMSO): δ 9.25 (s, 2H), 8.94 (d, J = 8.0Hz, 1H), 8.88 (d, J = 8.2Hz, 1H), 8.83 (d, J = 8.8Hz, 1H), 8.61 (d, J = 1.4Hz, 1H), 8.52 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.89 (dd, J = 1.7, 8.1Hz, 1H), 5.80 (d, J = 7.3Hz, 1H), 2.43 (s, 3H), 1.83 (d, J = 7.2Hz, 3H). LCMS (Method 3): [M+H] = 412.2 at 4.60 min.

[0651] Example 36

[0652] (R)-6-(5-methylthiazo-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-pyrido[3,2-d]pyrimidin-4-amine

[0653]

[0654] Nitrogen gas was used to bubble a mixture of (R)-6-bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine (intermediate 14) (100 mg, 0.25 mmol), potassium carbonate (69 mg, 0.501 mmol), 3-methyl-5-tributylmethylstannylthiazole (195 mg, 0.50 mmol), and cuprous iodide (9.5 mg, 0.05 mmol) in N,N-dimethylformamide (4.0 mL) for 5 min. Then, a complex of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane (41 mg, 0.05 mmol) was added. The reaction mixture was heated to 100 °C and held for 1 hour. After returning to room temperature, water (10 mL) was added, and the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were filtered through a hydrophobic glass filter. The solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (6.8 mg, 7%) as a grayish-white solid.

[0655] 1 ¹H NMR (400MHz, DMSO): δ 9.24 (s, 2H), 8.59 (d, J = 8.0Hz, 1H), 8.53–8.48 (m, 2H), 8.24 (d, J = 8.8Hz, 1H), 7.79 (d, J = 1.1Hz, 1H), 5.76–5.71 (m, 1H), 2.58 (s, 3H), 1.82 (d, J = 7.0Hz, 3H). LCMS (Method 3): [M+H] = 418.2 at 4.20 min.

[0656] Intermediate 15

[0657] 6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4(3H)-one

[0658]

[0659] Nitrogen gas was used to prepare 6-bromopyrido[3,2-d]pyrimidin-4(3H)-one (286 mg, 1.27 mmol), potassium carbonate (252 mg, 3.80 mmol), and 4-fluoro(phenylboronic acid) (195 mg, 1.40 mmol) in 1,4-dioxane. The mixture was bubbled for 15 minutes in a mixture of alkyl (5 mL) and water (0.5 mL), and then a complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride with dichloromethane (93 mg, 0.127 mmol) was added. The reaction mixture was sealed and heated to 110 °C in a microwave reactor and held for 30 minutes. After returning to room temperature, water (5 mL) was added and the reaction mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with brine (10 mL) and passed through a hydrophobic glass frit. The solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with a solution of 0–15% methanol in dichloromethane to give the title compound (294 mg, 96%) as a red powder.

[0660] LCMS (Method 4): [M+H] = 242.0 at 3.15 min.

[0661] Example 37

[0662] (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine

[0663]

[0664] Add (benzotriazol-1-yloxy)tripyrrolidinephosphine sequentially to a solution of 6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (intermediate 15) (150 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL). Hexafluorophosphate (356 mg, 0.68 mmol) and diisopropylethylamine (2.7 mL, 15.6 mmol) were added. The resulting mixture was heated to 50 °C and held for 1 hour, then (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethane-1-amine hydrochloride (156 mg, 0.68 mmol) was added and heating was maintained at 50 °C for 2 hours. After returning to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (10 mL). The organic phase was washed with brine (2 × 20 mL), passed through a hydrophobic glass frit, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (13 mg, 5%) as a grayish-white solid.

[0665] 1 ¹H NMR (400MHz, DMSO): δ 9.21 (s, 2H), 8.53–8.44 (m, 4H), 8.19 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.8, 8.8 Hz, 2H), 5.74 (q, J = 6.9 Hz, 1H), 2.07 (s, 1H), 1.81 (d, J = 7.0 Hz, 3H). LCMS (Method 3): [M+H] = 414.4 at 4.96 min.

[0666] The following compounds were synthesized according to the same procedure described in the preparation of (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine:

[0667]

[0668] Intermediate 16

[0669] 6-Bromopterin-4(3H)-one

[0670]

[0671] Acetic anhydride (10 mL, 105.79 mmol) was added to a suspension of 3-amino-6-bromopyrazin-2-carboxamide (2 g, 9.22 mmol) in triethyl orthoformate (20 mL, 120.24 mmol). The reaction mixture was heated to 120 °C and held at 1 h, then at 90 °C for 2 days. After returning to room temperature, the reaction mixture was concentrated under vacuum. The residue was ground in IPA, filtered, and dried to give the title compound (1.3 g, 62%) as a brown solid.

[0672] LCMS (Method 4): [MH+] = 227.0 at 1.81 min.

[0673] Intermediate 17

[0674] 6-(4-Fluorophenyl)pterin-4(3H)-one

[0675]

[0676] Place 6-bromopterin-4(3H)-one (intermediate 16) (300 mg, 1.32 mmol), potassium carbonate (548 mg, 3.96 mmol), 4-fluorophenylboronic acid (203 mg, 1.45 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (97 mg, 0.132 mmol) in a microwave-safe bottle. Add di... Alkane (5 mL) and water (0.5 mL) were added, and the solution was degassed with nitrogen for 10 minutes. The reaction mixture was heated to 110 °C in a microwave reactor and held for 35 minutes. After returning to room temperature, water (5 mL) was added, and the mixture was extracted with a mixture of CHCl3 / IPA (60:40) (3 × 20 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under vacuum to give the title compound (280 mg, 88%) as a red solid.

[0677] LCMS (Method 4): [MH+] = 243.0 at 2.93 min.

[0678] Example 39

[0679] 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridine-4-amine

[0680]

[0681] Step 1: Preparation of 4-chloro-6-(4-fluorophenyl)pteridine

[0682]

[0683] To a solution of 6-(4-fluorophenyl)pterin-4(3H)-one (intermediate 17) (280 mg, 1.16 mmol) in thionyl chloride (2.6 mL, 35.98 mmol), N,N-dimethylformamide (0.1 mL, 0.01 mmol) was added, and the mixture was refluxed and heated for 3 hours. After returning to room temperature, toluene (5 mL) was added, and the solvent was removed under vacuum. Toluene was added twice more, and the mixture was evaporated under vacuum to give the title compound, which was used for the next step without further purification.

[0684] Step 2: Preparation of 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridine-4-amine

[0685] 4-Chloro-6-(4-fluorophenyl)pteridine (120 mg, 0.460 mmol), 6-methylpyridazin-3-yl)methylamine dihydrochloride (81 mg, 0.506 mmol), and triethylamine (0.19 mL, 1.38 mmol) were dissolved in isopropanol (2.0 mL) and heated to 70 °C for 3 hours. The mixture was then cooled to room temperature and loaded onto an SCX column. The column was washed with methanol, and the filtrate was collected while eluting with a solution of 7 M ammonia in methanol. The solvent was removed under vacuum, and the residue was purified by preparative HPLC to give the title compound (8.6 mg, 7% yield).

[0686] 1 ¹H NMR (400MHz, CDCl₃): δ 9.48 (s, 1H), 8.81 (s, 1H), 8.36 (s, 1H), 8.16 (dd, J = 5.3, 8.6Hz, 2H), 7.53 (d, J = 8.6Hz, 1H), 7.36 (d, J = 8.6Hz, 1H), 7.25–7.22 (m, 2H), 5.18 (d, J = 5.6Hz, 2H), 2.75 (s, 3H). LCMS (Method 4): [MH⁺] = 348.0 at 3.17 min.

[0687] Example 40

[0688] 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)pteridine-4-amine

[0689]

[0690] Add (benzotriazol-1-yloxy)tripyrrolidinephosphine sequentially to a solution of 6-(4-fluorophenyl)pteridin-4(3H)-one (intermediate 17) (40 mg, 0.165 mmol) in N,N-dimethylformamide (4 mL). Hexafluorophosphate (95 mg, 0.18 mmol), diisopropylethylamine (0.71 mL, 4.1 mmol), and 1-(3-methyl-1,2,4-) (Diazol-5-yl)ethane-1-amine hydrochloride (36 mg, 0.18 mmol). The resulting mixture was heated to 50 °C and held for 2 hours. After returning to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were passed through a hydrophobic glass frit and the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the title compound (113 mg, 12%) as a yellow solid.

[0691] 1¹H NMR (400MHz, DMSO): δ 9.81 (s, 1H), 9.46 (d, J = 8.2Hz, 1H), 8.67–8.60 (m, 3H), 7.47 (dd, J = 8.9, 8.9Hz, 2H), 5.94–5.88 (m, 1H), 2.35 (s, 3H), 1.81 (d, J = 7.2Hz, 3H). LCMS (Method 3): [MH+] = 352.2 at 3.93 min.

[0692] According to the information regarding 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4- The following compounds reported in the table below were prepared using the same procedure described in the preparation of diazol-5-yl)ethyl)pteridine-4-amine:

[0693]

[0694] The following compounds, reported as single isomers, were obtained by chiral preparative SFC purification of the appropriate racemic mixture described above.

[0695]

[0696]

[0697]

[0698]

[0699]

[0700] The pharmacological activities of the compounds of this invention.

[0701] In vitro electrophysiological assays of P2X3

[0702] Cells expressing the P2X3 receptor were cultured according to standard practice and maintained at 37°C in a 5% humidified CO2 atmosphere. Two days before the assay, cells were seeded into T175 flasks and dissociated from the flasks using TrypLE when they reached 80-90% confluence. The dissociated cells were then divided into 3 x 10⁻⁶ cells per flask. 6Cells were resuspended at a density of 10 cells / ml in serum-free medium and loaded onto the Sophion Qube automated patch clamp system. Extracellular assay buffer contained 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose at pH 7.4. Intracellular assay solution contained 140 mM CsF, 10 mM NaCl, 10 mM EGTA, and 10 mM HEPES at pH 7.2. Agonist stock solutions were prepared in H2O and diluted in bath solution before use. All antagonists were prepared as 10 mM stock solutions in DMSO and diluted in bath solution before use. All experiments were performed at room temperature in a whole-cell patch clamp configuration, where 384 single cells were simultaneously voltage-clamped at -60 mV on the Sophion Qube instrument. Two baseline responses were established using α,β-MeATP (800 nM), and subsequent agonist applications were washed out using extracellular assay buffer containing 0.5 U / ml adenosine triphosphate bisphosphatase. Following the second agonist application, the antagonist was incubated for 10 minutes in the absence of α,β-MeATP. After antagonist pre-incubation, 800 nM α,β-MeATP and the antagonist were co-administered to determine the inhibitory effect of the antagonist. One concentration of the antagonist was evaluated for single-cell assessment, while different concentrations of the antagonist were applied to other cells on the 384 recording substrate. The control P2X3 current amplitude was taken from the peak current amplitude of the second agonist response prior to antagonist pre-incubation. Using the peak P2X3 current amplitude in the presence of the antagonist, the inhibitory effect at each antagonist concentration was calculated according to the following equation:

[0703] The percentage of P2X3 inhibition = (P2X3 control peak amplitude - P2X3 antagonist peak amplitude) / P2X3 control peak amplitude) * 100.

[0704] Concentration-response curves were constructed for ten different concentrations, with each antagonist concentration tested on at least two single cells. The antagonist concentration (IC50) that inhibited the P2X3 current by 50% was determined by fitting the data to the following equation. 50 ):

[0705] Y=a+[(ba) / (1+10^((log cx)d)]

[0706] Where 'a' is the minimum response, 'b' is the maximum response, and 'c' is the IC. 50 And 'd' is the slope of Hill.

[0707] Results for various compounds are provided in Table 8 below and expressed as activity ranges.

[0708] Table 8

[0709]

[0710]

[0711]

[0712]

[0713]

[0714] The compounds are classified according to the following criteria regarding their efficacy in inhibiting the P2X3 isoform:

[0715] +++:pIC 50 hP2X3>6.5

[0716] ++:6.5 <pIC 50 hP2X3>5.5

[0717] +:5.5 <pIC 50 hP2X3>4.5

[0718] P2X 2 / 3 In vitro electrophysiological assays

[0719] For P2X 2 / 3 The assay used the same assay protocol as the P2X3 assay, but with two adjustments: 1) 10 μM ATP was used as the agonist; and 2) the average current amplitude was measured 7 seconds after the agonist was applied.

[0720] The results in Table 9 indicate that the representative compound of the present invention is a selective P2X3 antagonist.

[0721] Table 9

[0722]

[0723]

[0724] The compounds are classified according to the following criteria regarding their relationship with P2X3 and P2X. 2 / 3 Classify the efficacy of the same type of inhibitory activity:

[0725] +++:pIC 50 hP2X3 or hP2X 2 / 3 >6.5

[0726] ++:6.5 <pIC 50 hP2X3 or hP2X 2 / 3 >5.5

[0727] +:5.5 <pIC 50 hP2X3 or hP2X 2 / 3 >4.5

[0728] Comparative Example A

[0729] 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine

[0730]

[0731] Step 1: Synthesis of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine

[0732]

[0733] 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (202 mg, 0.89 mmol) (intermediate 1), 5-hydroxymethyl-2-methylpyridine (110 mg, 0.89 mmol), and triphenylphosphine (328 mg, 1.25 mmol) were stirred in dry THF (7 mL), and a solution of diisopropyl azodicarbonate (229 μL, 1.16 mmol) in dry THF (3 mL) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the precipitate was washed with (2:1) DCM / MeOH (20 mL). The filtrates were combined and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel, eluting with a solution of 0-100% EtOAc in DCM to give 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidin (164 mg, 55%).

[0734] 1 H NMR (400MHz, DMSO): δ9.08(d,J=2.6Hz,1H),8.89(s,1H),8.67(d,J=2.6Hz,1H),8.55(d,J =2.1Hz, 1H), 7.72 (dd, J = 2.4, 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 5.20 (s, 2H), 2.44 (s, 3H).

[0735] Step 2: Synthesis of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine

[0736]

[0737] A mixture of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine (84 mg, 0.254 mmol), 4-fluorophenylboronic acid, pinacol ester (76 mg, 0.342 mmol), and cesium fluoride (116 mg, 0.761 mmol) in DMF (1 mL) and water (0.3 mL) was bubbled under nitrogen. After 5 min, tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added, and the resulting mixture was heated at 95 °C for 16 h. The reactants were diluted with water (6 mL) and EtOAc (3 mL). The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were passed through a hydrophobic glass frit, combined, and the solvent was removed under vacuum. 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine (52 mg, 59%) was purified by reversed-phase preparative HPLC as a 0.5 equivalent formate.

[0738] 1 H NMR (400MHz, DMSO): δ9.35(d,J=2.8Hz,1H),8.92(s,1H),8.73(d,J=2.5Hz,1H),8.61(d,J=1.5Hz,1H),8.32(s,0.5H),7.97(dd ,J=5.3,8.6Hz,2H),7.77(dd,J=2.1,8.0Hz,1H),7.42(dd,J=8.8,8.8Hz,2H),7.29(d,J=8.1Hz,1H),5.27(s,2H),2.49(s,3H).

[0739] LCMS (Method 4): [MH+] = 347 at 2.82 min.

[0740] The following compounds, reported in the table below, were prepared according to the same procedure described for the preparation of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine.

[0741]

[0742] The activity of comparative examples A and B has been tested in in vitro electrophysiological assays of P2X3 as described above.

[0743] Results for various compounds are provided in Table 10 below and expressed as activity ranges.

[0744] Table 10

[0745] Comparative Example Number <![CDATA[h P2X3]]> A Inactive B Inactive

[0746] Inactive: pIC50 h P2X3<4.5。

Claims

1. A compound of formula (la) wherein Z is aryl, said aryl being optionally substituted by one or more groups selected from (Ci-C3)alkyl, halo, CN; R1 is H; R2is selected from the group consisting of heteroaryl(Ci-C4)alkyl-, (C3-C8)heterocycloalkyl-(Ci-C6)alkyl, wherein any of such alkyl, heteroaryl groups can be optionally substituted with one or more groups selected from (Ci-C3)alkyl, halo, R A O(Ci-C4)alkylene-, (Ci-C6)haloalkyl, R A O-; J is H or (R A R B )N-; R A and R B independently at each occurrence is H or (C1-C4)alkyl-, or R A and R B may form, together with the nitrogen atom to which they are attached, a 6-membered saturated heterocyclic monocyclic ring system, which optionally contains a further heteroatom which is nitrogen, which can be optionally substituted by R C (O)C-; R C is (C1-C6)alkyl; wherein said heteroaryl is a monocyclic aromatic residue containing one or more heteroatoms selected from S, N and O, or a residue comprising two such monocyclic rings, or one such monocyclic ring and a monocyclic aryl ring, which are fused by a common bond; said aryl is a monocyclic carbocyclic ring system having 6 ring atoms, wherein said ring is an aromatic ring; said (C3-C8)heterocycloalkyl is a saturated monocyclic (C3-C8)cycloalkyl, wherein at least one ring carbon atom is replaced by at least one heteroatom selected from N, S or O.

2. A compound selected from: (R)-6-(4-Fluorophenyl)-N-(l-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3- d]pyrimidin-4-amine, (R)-6-(4-Fluorophenyl)-N-(l-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3- d]pyrimidin-4-amine, N-((6-Methylpyridazin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine, N-((3,5-Difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4- amine, 6-(4-Fluorophenyl)-N-[(lR)-l-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4- d]pyrimidin-4-amine, 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridine-4-amine, 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-] [Diazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3- d]pyrimidin-4-amine, and the single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, and 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3- d]pyrimidin-4-amine, and the single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, and N-[(6-Methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin- 4-amine, 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-) diazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 6-(4-Fluorophenyl)-N-[(lR)-l-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]pyrido[2,3- d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-] [diazol-2-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4- diazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[(3-methylis azol-5-yl)methyl]pyrido[2,3- d]pyrimidin-4-amine, 6-(4-Fluorophenyl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4- amine, 6-(4-fluorophenyl)-N-[(5-methyl-1,2,4-] [diazol-3-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-Fluorophenyl)-N-[(5-methyl-l,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin- 4-amine, 6-(4-fluorophenyl)-N-[(3-methyl-1,2,4-] [diazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[[3-(trifluoromethyl)-1,2,4- oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine, 6-Phenyl-N-[(lR)-l-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin- 4-amine, 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3- d]pyrimidin-4-amine, and the single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5- yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, and 6-(4-Fluorophenyl)-N-(l-(5-methyl-l,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin- 4-amine, single enantiomer 1, 6-(4-Fluorophenyl)-N-(l-(5-methyl-l,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin- 4-amine, single enantiomer 2, N-[l-(3,5-Difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4- amine, single enantiomer 1, the single enantiomer of N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3- d]pyrimidin-4-amine, and N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3- d]pyrimidin-4-amine.

3. A compound selected from: 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-] [Diazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3- d]pyrimidin-4-amine, and the single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, and 6-(4-fluorophenyl)-N-[l-(3-methyl-l,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3- d]pyrimidin-4-amine; and the single enantiomer 2 of 6-(4-fluorophenyl)-N-[l-(3-methyl-l,2,4-oxadiazol-5- yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine; and (R)-5-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2- (trifluoromethyl)pyridine 1-oxide; (R)-6-(4-Fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3- d]pyrimidin-4-amine; (S)-2-((6-(4-Fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(6- methoxypyridin-3-yl)ethan-1-ol; 6-(4-Fluorophenyl)-N-(2-morpholinoethyl)pyrido[2,3-d]pyrimidin-4-amine formate; (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3- d]pyrimidin-4-amine; N-((6-Methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine; 6-(4-Fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4- amine; 2-(4-(((6-Methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzonitrile; 2-(4-(((6-Methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzamide; N-((3,5-Difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4- amine; 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4- amine; 1-(4-(6-(4-Fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3- d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one; 1-(4-(4-(((6-Methylpyridazin-3-yl)methyl)amino)-6-(5-methylpyridin-2-yl)pyrido[2,3- d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one; N-[(6-Methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4- amine, 2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(5-methyl-1,2,4-yl) (diazol-3-yl)ethane-1-ol, (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-) diazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 6-(4-Fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin- 4-amine, (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-) diazol-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-) (diazol-5-yl)propane-2-yl)pyrido[2,3-d]pyrimidin-4-amine N-(1-(3,5-Difluoropyridin-2-yl)ethyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4- amine, 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-) diazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]pyrido[2,3- d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-] [diazol-2-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4- diazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[(3-methylis azol-5-yl)methyl]pyrido[2,3- d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(5-methyl-1,2,4-] [diazol-3-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4- amine, 6-(4-fluorophenyl)-N-[(3-methyl-1,2,4-] [diazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine 6-(4-fluorophenyl)-N-[[3-(trifluoromethyl)-1,2,4- oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3- d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3- d]pyrimidin-4-amine, and the single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5- yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, and 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4- amine, single enantiomer 1, 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4- amine, single enantiomer 2, N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine, single enantiomer 1, N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine, single enantiomer 2, and N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine.

4. A compound selected from: 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine; 6-(4-fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4- d]pyrimidin-4-amine; 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine; (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2- d]pyrimidin-4-amine; 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine.

5. A compound selected from: 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridine-4-amine; 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-) Diazol-5-yl)ethyl)pteridine-4-amine; (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pteridine-4- amine; 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pteridine-4-amine.

6. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-5, alone or in combination with another active ingredient or ingredients, in admixture with one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6 for oral administration.

8. Use of a compound according to any one of claims 1-5 or of a pharmaceutical composition according to any one of claims 6 and 7 for the manufacture of a medicament for the treatment of any disease wherein P2X3 receptors are involved.

9. Use of a compound according to any one of claims 1-5 or of a pharmaceutical composition according to any one of claims 6 and 7 for the manufacture of a medicament for the prevention and / or treatment of a respiratory disease selected from the group consisting of cough, asthma, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

10. Use of a compound according to any one of claims 1-5 or of a pharmaceutical composition according to any one of claims 6 and 7 for the manufacture of a medicament for the prevention and / or treatment of a respiratory disease selected from the group consisting of treatment resistant cough, idiopathic chronic cough, post viral cough, iatrogenic cough and cough associated with a respiratory disease selected from the group consisting of chronic obstructive pulmonary disease, asthma and bronchospasm.

11. Use of a compound according to any one of claims 1-5 or of a pharmaceutical composition according to any one of claims 6 and 7 for the manufacture of a medicament for the prevention and / or treatment of a respiratory disease selected from the group consisting of subacute cough and chronic cough.

12. Use according to claim 11 wherein the respiratory disease is chronic cough.

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