RU2833037C2 - Pyridopyrimidine derivatives as p2x3 inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds selected from (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine, (R)-6-(5-methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, (R)-6-(5-chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, (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, N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine, N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine-4-amine, 6-(4-fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine, and so forth, which have an inhibitory effect on purinergic receptor 3 (P2X₃). Invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: compounds can find application in treating a disease in which P2X₃ receptors are involved.

11 cl, 10 tbl, 107 ex

Description

AREA OF TECHNOLOGY

The present invention relates to compounds that inhibit P2X purinergic receptor 3 (hereinafter P2X ₃ inhibitors); in particular, the invention relates to compounds that are derivatives of pyridopyrimidines, methods for producing such compounds, pharmaceutical compositions containing them, and their therapeutic use.

The compounds of the invention can be used in the treatment of many disorders associated with P2X ₃ receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

LEVEL OF TECHNOLOGY

P2X receptors are cell surface ion channels activated by extracellular adenosine-5-triphosphate (ATP). The P2X receptor family is a trimeric assemblage of seven distinct subunit subtypes (P2X1-7) that assemble as homomeric and heteromeric channels. All subunits share a common topology containing intracellular termini, two transmembrane helices forming the ion channels, and a large extracellular domain containing an ATP binding site. The homomeric channels _P2X1 , _P2X2 , _P2X3 , _P2X4 , _P2X5 , and _P2X7 and the heteromeric channels P2X2 _/3 and P2X1 _/5 have been fully characterized following heterologous expression. P2X receptors are widely distributed and functional responses are observed in neurons, glia, epithelia, endothelium, bone, muscle, and hematopoietic tissues. On smooth muscle, P2X receptors respond to ATP released from sympathetic motor nerves (eg, during ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several visceral organs (eg, bladder, intestine) and play a key role in the perception of tissue injury and inflammation stimuli. A paracrine role in ATP signaling via P2X receptors is likely in the neurohypophysis, ductal glands, airway epithelium, kidney, bone, and hematopoietic tissues. (RA. North: Molecular Physiology of P2X Receptors; Physiol Rev, Vol 82, Oct 2002). All P2X receptors are non-selective cation channels permeable to Na+ and Ca+ ions and are activated by ATP; however, the pharmacology of receptor subtypes varies depending on their sensitivity to ATP and to small molecule antagonists. (K Kaczmarek-Hajek et al: Molecular and functional properties of P2X receptors - recent progress and persisting challenges; Purinergic Signalling 8: 375-417, 2012).

In humans, the P2X ₃ receptor has been detected in the heart and spinal cord at the mRNA level, and in the DRG, intestine (neurons of the myenteric plexus), bladder (urothelium and suburothelium), and dental pulp at the protein level (Garcia-Guzman M et al: Molecular characterization and pharmacological properties of the human P2X ₃ purinoceptor: Brain Res Mol Brain Res. 1997; 47(1-2): 59-66).

The neurophysiological role of P2X ₃ receptors in airway sensory nerve function is similar to that mediating somatic nociception (Undem BJ and Nassenstein C: Airway nerves and dyspnea associated with inflammatory airway disease, Respir Physiol Neurobiol 167: 36–44, 2009). This similarity has led to hypotheses involving P2X ₃ receptors in symptoms of airway dysfunction, including cough and bronchial hyperreactivity (Ford AP: In pursuit of P2X ₃ antagonists: novel therapeutics for chronic pain and afferent sensitization, Purinergic signal 8 (suppl 1): 3–26, 2012; North RA, Jarvis MF P2X Receptors as Drug Targets; Mol Pharmacol, 83: 759–769, 2013). P2X ₃ subunits also co-localize in many neurons, particularly in the DRG, nodose ganglia, nucleus of the solitary tract, and taste buds (Cheung KK, Burnstock G: Localization of P2X ₃ receptors and coexpression with P2X ₂ receptors during rat embryonic neurogenesis. J Comp Neurol 443(4): 368-382 2002).

P2X ₃ antagonists have been proposed for the treatment of diabetic neuropathic pain (Guo J et al: Contributions of purinergic P2X ₃ receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain, J Physiol Sci Jan; 65(1): 99-104 2015).

P2X ₃ and P2X _2/3 channels play an important role in the development of articular hyperalgesia in arthritic joints (Teixeira JM et al: P2X ₃ and P2X _2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis, Mol Neurobiol Oct; 54(8): 6174-6186, 2017).

P2X ₃ are also a potential target for the therapeutic treatment of bladder pain. They have also been proposed as analgesic targets for the treatment of ureteral colic pain and for facilitating the passage of ureteral stones (Canda AE et al: Physiology and pharmacology of the human ureter: basis for current and future treatments, Urol Int. 78(4): 289-98, 2007).

Overexpression of P2X ₃ is involved in poor recurrence-free survival in patients with hepatocellular carcinoma and identifies P2X ₃ as a potential therapeutic target (Maynard JP et al: P2X ₃ purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients Oncotarget Dec 1; 6(38): 41162-79, 2015).

It has been suggested that P2X ₃ antagonists may improve recovery of erectile function (Li CL et al: Effects of intracavernous injection of P2X ₃ and NK1 receptor antagonists on erectile dysfunction induced by spinal cord transection in rats, Andrologia . Feb; 47(1): 25-9, 2015).

ATP enhances citric acid- and histamine-induced cough in preclinical models, effects that can be attenuated by selective P2X ₃ antagonists (Kamei J and Takahashi Y: Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs, Oct 10;547(1-3): 160-4, 2006). In humans, local delivery of ATP induces 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).

The therapeutic promise of P2X ₃ antagonists for the treatment of chronic cough was first recognized by Ford and Undem (Ford AP, Undem BJ: The therapeutic promise of ATP antagonism at P2X ₃ receptors in respiratory and urological disorders, Front Cell Neurosci, Dec 19;7:267, 2013). P2X ₃ are expressed by airway afferent nerves and mediate cough reflex hypersensitivity, which is dramatically reduced by the oral P2X ₃ antagonist, AF-219 (Abdulqawi et al: P2X ₃ receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study, Lancet 385, 1198–205, 2015).

ATP is a key neurotransmitter in the taste system, acting primarily through the P2X _2/3 heteromultimer receptors. Therefore, taste dysfunction may be an unintended consequence of therapeutic trials of P2X ₃ purinergic antagonists for pain, chronic cough, and other conditions (Vandenbeuch A et al: Role of the ectonucleotidase NTPDase2 in taste bud function, Proc Natl Acad Sci USA, Sep 3; 110(36): 14789–94, 2013. Bo X et al: Localization of ATP-gated P2X2 and P2X ₃ receptor immunoreactive nerves in rat taste buds, Neuroreport, 10(5): 1107–11, 1999).

Various compounds have been described in the literature as P2X ₃ and/or P2X _2/3 inhibitors.

WO 2017058645 (Afferent Pharmaceuticals INC) describes the use of diaminopyrimidine P2X ₃ /P2X _2/3 antagonists for the treatment of disorders including cough, chronic cough and coughing urge, including cough associated with a respiratory disease or disorder, by administering an effective amount of the disclosed compound. However, pyridopyrimidine derivatives are not disclosed.

WO 2017011729 (Patara Pharma LLC) describes the use of cromolyn or a pharmaceutically acceptable salt thereof and a P2X ₃ and/or P2X _2/3 receptor antagonist as an antitussive agent for the treatment of lung diseases and conditions.

WO 2016091776 (Evotec AG) describes 1,3-thiazol-2-yl-substituted benzamide compounds that inhibit the P2X ₃ receptor and pharmaceutical compositions containing such compounds, as well as the use of the compounds for the treatment of certain diseases, including respiratory diseases.

WO 2016088838 (Shionogi) describes purine derivative compounds having a novel antagonist effect on P2X ₃ and/or P2X _2/3 receptors.

WO 2016084922, (Shionogi) describes triazine derivative compounds having a novel antagonist activity at P2X ₃ and/or P2X _2/3 receptors.

WO 2008123963 (Renovis) relates to fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions containing such compounds. Methods for the prevention and/or treatment of several disorders, such as neurodegenerative disorders, pain, asthma, autoimmune disorders, using the disclosed compounds are also provided.

WO 2008130481 (Renovis) describes 2-cyanophenyl fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions containing such compounds.

WO 2010033168 (Renovis) describes a series of phenyl or pyridyl substituted benzamides which are claimed to be useful for the treatment of diseases associated with purinergic P2X receptors, and more particularly with P2X receptor ₃ and/or P2X receptor _2/3 antagonists. However, pyridopyrimidine derivatives are not described.

WO 2009110985 (Renovis) relates to phenyl- and pyridyl-substituted benzamide compounds and pharmaceutical compositions containing such compounds, but not to thiazole-substituted benzamides, making these compounds different from the compounds of the present invention.

WO 2008000645 (Roche) describes tetrazole-substituted arylamide compound P2X ₃ and/or P2X _2/3 receptor antagonists useful for the treatment of genitourinary, pain, gastrointestinal and respiratory diseases, conditions and disorders.

There remains potential for the development of new and pharmacologically improved P2X ₃ and/or P2X _2/3 inhibitors in many therapeutic areas, such as, in particular, respiratory diseases.

Despite the above-cited prior art, there is still a need for new pyridopyrimidine compounds for the treatment of P2X ₃ receptor-associated diseases in many therapeutic areas, such as in particular respiratory diseases, preferably having a selective action on the P2X ₃ receptor.

It should be noted that the prior art does not describe or propose pyridopyrimidine derivatives of general formula (I) according to the present invention, which represent a solution to the above-mentioned need.

ESSENCE OF THE INVENTION

The present invention relates to compounds of formula (I)

where X ₁ , X ₂ and X ₃ are independently CH or N,

Z is H or is selected from the group consisting of (C ₁ -C ₄ )alkyl-, heteroaryl, aryl, wherein any of such heteroaryl and aryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen, CN, ( ^RA R ^B )NC(O)-;

R ₁ is H;

R ₂ is selected from the group consisting of heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )heterocycloalkyl-(C ₁ -C ₆ )alkyl-, wherein any of such alkyl, heteroaryl and heterocycloalkyl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halo, R ^A O(C ₁ -C ₄ )alkylene-, (C ₁ -C ₆ )haloalkyl, R ^A O-;

R ^A and R ^B are in each case independently H or (C ₁ -C ₄ )alkyl-, or

R ^A and R ^B together with the nitrogen atom to which they are attached may form a 6-membered saturated heterocyclic monocyclic ring system optionally containing an additional heteroatom which is nitrogen which may be optionally substituted with R ^C (O)C-;

R ^C is (C ₁ -C ₆ )alkyl;

J is H or (R ^A R ^B )N-.

In a second aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other active ingredients, in admixture with one or more pharmaceutically acceptable carriers or excipients.

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

In a further aspect, the invention provides the use of a compound of formula (I) for the treatment of any disease in which P2X ₃ receptors are involved.

In a further aspect, the invention relates to a compound of formula (I) for use in the prevention and/or treatment of respiratory diseases, including cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

In a further aspect, the invention relates to a compound of formula IIIa.

where X is N or CH,

R ₇ is OH and/or Cl;

R ₈ is a halogen.

In a further aspect, the invention relates to the use of a compound of formula (IIIa) as an intermediate in the preparation of compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a compound of formula (I)

where X ₁ , X ₂ and X ₃ are independently CH or N,

Z is H or is selected from the group consisting of (C ₁ -C ₄ )alkyl-, heteroaryl, aryl, wherein any of such heteroaryl and aryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen, CN, ( ^RA R ^B )NC(O)-;

R ₁ is H;

R ₂ is selected from the group consisting of heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )heterocycloalkyl-(C ₁ -C ₆ )alkyl-, wherein any of such alkyl, heteroaryl and heterocycloalkyl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen, R ^A O(C ₁ -C ₄ )alkylene-, (C ₁ -C ₆ )haloalkyl, R ^A O-;

R ^A and R ^B are in each case independently H or (C ₁ -C ₄ )alkyl-, or

R ^A and R ^B together with the nitrogen atom to which they are attached may form a 6-membered saturated heterocyclic monocyclic ring system optionally containing an additional heteroatom which is nitrogen which may be optionally substituted with R ^C (O)C-;

R ^C is (C ₁ -C ₆ )alkyl;

J is H or is selected from the group consisting of (R ^A R ^B )N-.

DEFINITIONS

The term "pharmaceutically acceptable salts" as used herein refers to derivatives of the compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid generally considered pharmaceutically acceptable.

Thus, suitable examples of said salts may include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic base addition salts of acidic residues such as carboxyl groups.

Inorganic base cations that can be suitably used to form salts include alkali or alkaline earth metal ions such as potassium, sodium, calcium or magnesium.

Compounds obtained by reacting a basic compound acting 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.

The term "halogen" or "halogen atoms" in the present description includes fluorine, chlorine, bromine and iodine atom, preferably chlorine or fluorine.

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

As used herein, the term "(C _x -C _y ) alkylene", where x and y are integers, refers to a C _x -C _y alkyl radical having only two unsaturated valences, such as the divalent methylene radical.

The expressions "(C _x -C _y ) haloalkyl", where x and y are integers, refer to the above-defined "C _x -C _y alkyl" groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different.

Examples of the said "(C _x -C _y )haloalkyl" groups may thus include halogenated, polyhalogenated and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, for example trifluoromethyl or difluoromethyl, trifluoroethyl groups.

By analogy, the terms "(C ₁ -C ₆ ) hydroxyalkyl" or "(C ₁ -C ₆ ) aminoalkyl" refer to "(C ₁ -C ₆ ) alkyl" groups as defined above in which one or more hydrogen atoms are replaced by one or more hydroxy (OH) or amino groups, respectively. Examples include, respectively, hydroxymethyl, aminomethyl, dimethylaminopropyl, and the like.

In the present specification, unless otherwise specified, aminoalkyl embraces alkyl groups (i.e., "(C ₁ -C ₆ ) alkyl" groups) substituted with one or more amino groups (-NR ^A R ^B ). Thus, an example of aminoalkyl is a monoaminoalkyl group such as R ^A R ^B N-(C ₁ -C ₆ ) alkyl.

With respect to the substituent R ^A and R ^B as defined above and below, when R ^A and R ^B are taken together with the nitrogen atom to which they are bonded to form a 5-6-membered heterocyclic radical, at least one additional ring carbon atom in said heterocyclic radical is optionally substituted by at least one heteroatom (e.g. N, S or O) and/or may bear -oxo (=O) substituent groups. It is understood that said heterocyclic radical may be further optionally substituted at any available position in the ring, namely at a carbon atom, or at any heteroatom available for substitution. Substitution at a carbon atom includes spiro disubstitution as well as substitution at two adjacent carbon atoms, thus in both cases an additional 5-6-membered heterocyclic ring is formed. Examples of the said heterocyclic radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, piperazin-4-yl-2-one, 4-morpholinyl, morpholinyl-3-one, 1-(piperazin-1-yl)ethenone.

The term "(C _x -C _y ) cycloalkyl", where x and y are integers, refers to saturated cyclic hydrocarbon groups containing the stated number of carbon atoms in the ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

The term "aryl" refers to monocyclic carbon ring systems that have 6 ring atoms, where the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

The term "heteroaryl" refers to a mono- or bicyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are fused through a common bond. Examples of suitable 5,6-membered heteroaryl are: thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinyl, tetrazolyl and triazinyl.

The term "heterocyclyl" or "heterocyclic" refers to a saturated mono-, bi- or tricyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O. In the case of bicyclic heterocyclic systems, fused, spiro and bridged bicyclic systems are included within the scope of the term.

The term "(C _x -C _y ) heterocycloalkyl", where x and y are integers, refers to saturated or partially unsaturated monocyclic (C _x -C _y ) cycloalkyl groups in which at least one ring carbon atom is substituted by at least one heteroatom (e.g., N, S or O) or may bear a -oxo (=O) substituent group. Said heterocycloalkyl (i.e., heterocyclic radical or group) may be further optionally substituted at available positions in the ring, namely, on a carbon atom or on a heteroatom available for substitution. Substitution on a carbon atom includes spiro disubstitution as well as substitution on two adjacent carbon atoms, in both cases thereby forming an additional fused 5-6-membered heterocyclic ring. Examples of (C _x -C _y ) heterocycloalkyl are: pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydropyridinyl, tetrahydrothiophenyl, azetidinyl, oxetanyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-onyl, dihydropyrrolyl radicals and the like.

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

The expressions "aryloxyl" and "aryl(C ₁ -C ₆ )alkoxyl" and "heteroaryloxyl" and "heteroaryl(C ₁ -C ₆ )alkoxyl" refer to aryl or heteroaryl groups attached through an oxygen bridge and linked aryl-alkoxyl or heteroaryl-alkoxyl groups. Examples of such groups are phenyloxy, benzyloxy and pyridinyloxy, respectively.

The term "aryl( _C1 - _C6 )alkyl" refers to an aryl ring bound to straight or branched alkyl groups where the number of carbon atoms is from 1 to 6, such as phenylmethyl (i.e., benzyl), phenylethyl, or phenylpropyl.

The term (C _z -C _k ) heterocycloalkyl-(C _x -C _y ) alkyl, where z and k are integers, refers to a heterocyclic ring bound to straight or branched alkyl groups having from x to y carbon atoms.

Similarly, the term "heteroaryl(C _x -C _y )alkyl" or "aryl(C _x -C _y )alkyl" refers to a heteroaryl or aryl ring bound to straight or branched alkyl groups having from x to y carbon atoms.

The expression "ring system" refers to mono- or bicyclic or polycyclic ring systems which may be saturated, partially unsaturated or unsaturated, such as aryl, ( _C3 - _C10 )cycloalkyl, ( _C3 - _C6 )heterocycloalkyl or heteroaryl.

The terms "group", "radical", "moiety" or "substituent" are synonymous and are intended to denote functional groups or moieties of molecules that may be attached to a bond or other moieties or molecules. Thus, as an example, "heterocyclic radical" as used herein refers to a mono- or bicyclic saturated or partially saturated heterocyclic moiety (group, radical), preferably a 4- to 11-membered monocyclic radical, wherein at least one additional ring carbon atom in said heterocyclic radical is optionally substituted with at least one additional heteroatom independently selected from N, S or O, and/or may bear a -oxo (=O) substituent group, wherein said heterocyclic radical further optionally includes spiro disubstitution as well as substitution on two adjacent or vicinal atoms forming an additional 5- to 6-membered cyclic or heterocyclic, saturated, partially saturated or aromatic ring. Examples of the said heterocyclic radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and the like.

A dash ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. In graphical representation, the point of attachment in a cyclic functional group is indicated by a dot ("•") located at one of the available ring atoms where the functional group can attach to a bond or other molecular fragment.

The oxo group is represented by (O) as an alternative to another common representation, such as (=O). Thus, in terms of the general formula, the carbonyl group is here represented as -C(O)-. In general, a group in parentheses represents a side group not included in the chain, and parentheses are used when they are considered useful to help disambiguate linear chemical formulas; for example, the sulfonyl group -SO ₂ - may also be represented as -S(O) ₂ - to disambiguate, for example, with respect to the sulfine group -S(O)O-.

When basic amino or quaternary ammonium groups are present in the compounds of formula I, physiologically acceptable anions selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate may be present. Similarly, in the presence of acidic groups such as COOH groups, the corresponding physiological cationic salts, for example including alkali or alkaline earth metal ions, may also be present.

It is obvious that compounds of formula (I), if they contain one or more stereogenic centers, can exist in the form of optical stereoisomers.

If the compounds of the invention have at least one stereogenic center, they may accordingly exist as enantiomers. If the compounds of the invention have two or more stereogenic centers, they may additionally exist as diastereoisomers. All such individual enantiomers, diastereoisomers and mixtures thereof in any proportion are within the scope of the present invention. The absolute configuration (R) or (S) for the carbon bearing the stereogenic center is assigned based on the rules of the Cahn-Ingold-Prelog nomenclature based on group priorities.

The invention also relates to the corresponding deuterated derivatives of the compounds of formula (I).

All preferred groups or embodiments described above and below for the compounds of formula I can be combined with each other and also applied mutatis mutandis.

In a preferred embodiment, the invention is directed to compounds of formula (I) as defined above, wherein

X ₁ , X ₂ and X ₃ are independently CH or N,

Z is selected from the group consisting of

heteroaryl, preferably pyridinyl, thiazolyl and thienyl, and

aryl, preferably phenyl,

wherein any of such heteroaryl and aryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl and halogen, preferably from methyl, fluorine and chlorine;

R ₁ is H;

R ₂ is heteroaryl(C ₁ -C ₄ )alkyl-, preferably (pyridazyl)methyl, (pyridazyl)ethyl, (pyridinyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl, wherein any of such heteroaryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen and (C ₁ -C ₆ )haloalkyl, preferably from methyl, fluoro and trifluoromethyl; and

J is H.

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 1 below and pharmaceutically acceptable salts thereof.

Table 1: List of preferred compounds having formula (I) Example No. Structure Chemical name Example 3 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 7 N-((6-Methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 9 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 11 (R)-6-(5-Chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 13 (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 14 N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine Example 15 N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 19 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 27 6-(4-Fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine Example 32 N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]-pyrimidin-4-amine Example 34 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine Example 42 6-(4-Fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pteridin-4-amine Example 45 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 46 The only enantiomer of 2 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 49 6-(5-methylthiazol-2-yl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 50 6-(5-methylthiazol-2-yl)-N-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 51 N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 52 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 63 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 65 6-(5-methylpyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 66 (6-(5-Fluoro-2-pyridyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 67 (R)-6-(5-fluoropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 68 N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methylpyrimidin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 69 6-(4-fluorophenyl)-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 70 6-(5-fluoropyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 71 N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 72 N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 73 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 75 6-(5-methylthiazol-2-yl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 76 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 77 6-(4-fluorophenyl)-N-[(3-methylisoxazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 78 N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 79 6-(4-fluorophenyl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 80 6-(4-fluorophenyl)-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 82 N-[(3-methylisoxazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 83 The only enantiomer of 1 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 84 The only enantiomer of 2 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 87 The only enantiomer of 1 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 88 The only enantiomer of 2 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 91 6-(4-Fluorophenyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 92 6-(4-fluorophenyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 93 6-(4-fluorophenyl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 94 6-(5-chloro-2-pyridyl)-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 95 6-phenyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 102 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 103 The only enantiomer of 1 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 104 The only enantiomer of 2 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 105 The only enantiomer of 1 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 106 The only enantiomer of 2 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 63a N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 107 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine

In a preferred embodiment, the invention is directed to compounds of formula (I) as defined above, wherein X ₁ is N, X ₂ and X ₃ are CH, represented by formula (Ia)

Z is H or is selected from the group consisting of (C ₁ -C ₄ )alkyl-, heteroaryl, aryl, wherein any of such heteroaryl and aryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen, CN, ( ^RA R ^B )NC(O)-;

R1 is H;

R2 is selected from the group consisting of heteroaryl( _C1 - _C4 )alkyl-, ( _C3 - _C8 )heterocycloalkyl-( _C1 - _C6 )alkyl, where any of such alkyl, heteroaryl may be optionally substituted with one or more groups selected from ( _C1 - _C3 )alkyl, halogen, ^RAO ( _C1 - _C4 )alkylene-, ( _C1 - _C6 )haloalkyl, ^RAO- ;

R ^A and R ^B are in each case independently H or (C ₁ -C ₄ )alkyl-, or

R ^A and R ^B together with the nitrogen atom to which they are attached may form a 6-membered saturated heterocyclic monocyclic ring system optionally containing an additional heteroatom which is nitrogen which may be optionally substituted with R ^C (O)C-;

R ^C is (C ₁ -C ₆ )alkyl;

J is H or (R ^A R ^B )N-.

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

Z is H or selected from the group consisting of

(C ₁ -C ₄ )alkyl-, preferably methyl,

(R ^A R ^B )N-, where R ^A is H and R ^B is phenyl, wherein said phenyl is optionally further substituted with one or more fluorines;

heteroaryl which is pyridinyl, thiazolyl, thiophenyl, wherein each of said heteroaryl is further optionally substituted with one or more groups selected from methyl or chlorine;

aryl, preferably phenyl, wherein each of said aryl is further optionally substituted with one or more groups selected from methyl, fluoro, CN and (R ^A R ^B )NC(O)-, where R ^A and R ^B are H;

R ₁ is H;

R2 is selected from the group consisting of

heteroaryl(C ₁ -C ₄ )alkyl-, preferably (pyridazyl)methyl, (pyridazyl)ethyl, (pyridinyl)methyl, (pyridinyl)ethyl, (pyrimidyl)ethyl, (oxadiazolyl)ethyl,

heteroaryl (C ₁ -C ₆ ) alkoxy, preferably pyridinyloxy,

heteroaryl-(C ₁ -C ₆ )hydroxyalkyl, preferably (pyridinyl)ethanol,

(C ₃ -C ₈ )heterocycloalkyl-(C ₁ -C ₆ )alkyl, preferably (morpholinyl)ethyl,

each of said heteroaryls is optionally substituted with one or more groups selected from methyl, fluoro, trifluoromethyl, R ^A O-, where R ^A is methyl;

J is H or (R ^A R ^B )N-, where R ^A and R ^B together with the nitrogen atom to which they are attached form a 6-membered saturated heterocyclic monocyclic ring system optionally containing an additional heteroatom which is nitrogen, wherein said heterocyclic radical is in turn optionally further substituted with R ^C (O)C-, where R ^C is methyl.

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 2 below and pharmaceutically acceptable salts thereof.

Table 2: List of preferred compounds having formula (Ia) Example No. Structure Chemical name Example 1 6-(4-Fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 2 (R)-5-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide Example 3 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 4 (S)-2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(6-methoxypyridin-3-yl)ethan-1-ol Example 5 6-(4-fluorophenyl)-N-(2-morpholinoethyl)pyrido[2,3-d]pyrimidin-4-amine formate Example 6 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]-pyrimidin-4-amine Example 7 N-((6-Methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 8 6-(5-Chloropyridin-2-yl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 9 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 10 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 11 (R)-6-(5-Chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 12 6-(5-Chloropyridin-2-yl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 13 (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 14 N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine Example 15 N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 16 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 17 2-(4-(((6-methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzonitrile Example 18 2-(4-(((6-methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzamide Example 19 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 20 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 21 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 Example 22 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one Example 23 1-(4-(4-(((6-Methylpyridazin-3-yl)methyl)amino)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one Example 24 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 Example 25 1-(4-(6-Methyl-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one Example 49 6-(5-methylthiazol-2-yl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 50 6-(5-methylthiazol-2-yl)-N-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 51 N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 52 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 54 2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(5-methyl-1,2,4-oxadiazol-3-yl)ethan-1-ol Example 55 (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 56 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 58 (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 59 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 60 N-(1-(3,5-difluoropyridin-2-yl)ethyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 63 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 65 6-(5-methylpyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 66 (6-(5-Fluoro-2-pyridyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 67 (R)-6-(5-fluoropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 68 N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methylpyrimidin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 69 6-(4-fluorophenyl)-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 70 6-(5-fluoropyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 71 N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 72 N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 73 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 75 6-(5-methylthiazol-2-yl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 76 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 77 6-(4-fluorophenyl)-N-[(3-methylisoxazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 78 N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 79 6-(4-fluorophenyl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 80 6-(4-fluorophenyl)-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 82 N-[(3-methylisoxazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 83 The only enantiomer of 1 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 84 The only enantiomer of 2 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 87 The only enantiomer of 1 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 88 The only enantiomer of 2 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 91 6-(4-Fluorophenyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 92 6-(4-fluorophenyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine Example 93 6-(4-fluorophenyl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine Example 94 6-(5-chloro-2-pyridyl)-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 95 6-phenyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 102 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 Example 103 The only enantiomer of 1 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 104 The only enantiomer of 2 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 105 The only enantiomer of 1 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 106 The only enantiomer of 2 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 63a N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 107 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine

In an even more preferred embodiment, the invention further relates to a compound of formula (Ia), wherein

Z is selected from the group consisting of heteroaryl, aryl, wherein any of such heteroaryl and aryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen;

R1 is H;

R2 is selected from the group consisting of heteroaryl( _C1 - _C4 )alkyl, where any of such alkyl, heteroaryl may be optionally substituted with one or more groups selected from ( _C1 - _C3 )alkyl, halogen, ( _C1 - _C6 )haloalkyl, -oxo;

J is H.

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 3 below and pharmaceutically acceptable salts thereof.

Table 3: List of preferred compounds having formula (Ia) Example No. Structure Chemical name Example 1 6-(4-Fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 2 (R)-5-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide Example 6 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]-pyrimidin-4-amine Example 7 N-((6-Methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 9 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 10 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 11 (R)-6-(5-Chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 13 (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 14 N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine Example 15 N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 16 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 19 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 20 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine Example 43 The only enantiomer of 1 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 44 The only enantiomer of 2 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 45 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 46 The only enantiomer of 2 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 47 The only enantiomer of 1 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 48 The only enantiomer of 2 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine

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

Z is selected from the group consisting of phenyl, pyridinyl and thienyl, wherein any of such phenyl, pyridinyl and thienyl may be optionally substituted with one or more groups selected from methyl and fluoro;

R1 is H;

R2 is selected from the group consisting of heteroaryl( _C1 - _C2 )alkyl, wherein any such heteroaryl may be optionally substituted with one or more groups selected from methyl, fluoro and trifluoromethyl;

J is H.

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 4 below and pharmaceutically acceptable salts thereof.

Table 4: List of additional preferred compounds having formula (Ia) Example No. Structure Chemical name Example 3 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 7 N-((6-Methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 9 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 11 (R)-6-(5-Chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 13 (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine Example 14 N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine Example 15 N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine Example 19 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine Example 45 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine Example 46 The only enantiomer of 2 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine

In another preferred embodiment, the invention is directed to compounds of formula (I) as defined above, wherein X ₁ is CH, represented by formula Ib

where X ₂ and X ₃ are independently CH or N,

Z is selected from the group consisting of heteroaryl and aryl, wherein any of such aryl and heteroaryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, halogen;

R ₁ is H;

R ₂ is selected from the group consisting of heteroaryl(C ₁ -C ₄ )alkyl-, wherein any of such alkyl and heteroaryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )haloalkyl;

J is H.

In another preferred embodiment, the invention relates to a compound of formula Ib, wherein X ₂ and X ₃ are independently CH or N,

Z is selected from the group consisting of

heteroaryl which is pyridinyl, thiazolyl, wherein each of said heteroaryl is further optionally substituted with one or more methyl,

aryl which is phenyl, wherein each of said aryl is further optionally substituted with one or more fluorines;

R1 is H;

R2 is selected from the group consisting of

heteroaryl(C ₁ -C ₄ )alkyl-, which is (pyrimidyl)ethyl, (pyridazyl)methyl, (oxadiazolyl)ethyl,

each of said heteroarylalkyl is further optionally substituted with one or more groups selected from methyl and trifluoromethyl;

J is H.

According to preferred embodiments, the invention relates to at least one compound listed in Table 5 below and pharmaceutically acceptable salts thereof.

Table 5: List of preferred compounds having formula (Ib) Example No. Structure Chemical name Example 26 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine Example 27 6-(4-Fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine Example 28 N-[(6-Methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,4-d]pyrimidin-4-amine Example 29 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methyl-2-pyridyl)pyrido[3,4-d]pyrimidin-4-amine Example 30 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine Example 31 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine Example 32 N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]-pyrimidin-4-amine Example 33 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine Example 34 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine Example 35 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine Example 36 (R)-6-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-pyrido[3,2-d]pyrimidin-4-amine Example 37 (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine Example 38 6-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine

In another preferred embodiment, the invention relates to a compound of formula Ib wherein X ₂ and X ₃ are independently CH or N,

Z is selected from the group consisting of pyridinyl, thiazolyl and phenyl,

wherein each of said pyridinyl, thiazolyl and phenyl is optionally substituted with one or more groups selected from methyl and fluoro;

R1 is H;

R2 is selected from the group consisting of (pyrimidyl)ethyl and (pyridazyl)methyl,

wherein each of said (pyrimidyl)ethyl and (pyridazyl)methyl is optionally substituted with one or more groups selected from methyl and trifluoromethyl;

J is H.

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 6 below and pharmaceutically acceptable salts thereof.

Table 6: List of preferred compounds having formula (Ib) Example No. Structure Chemical name Example 27 6-(4-Fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine Example 32 N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]-pyrimidin-4-amine Example 34 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine

In another preferred embodiment, the invention is directed to compounds of formula (I) as defined above, wherein X ₁ and X ₃ are N and X ₂ is CH, represented by formula Ic

Z is selected from the group consisting of aryl and heteroaryl, wherein any of such aryl and heteroaryl may be optionally substituted with one or more groups selected from halogen and (C ₁ -C ₃ )alkyl;

R ₁ is H;

R ₂ is selected from the group consisting of heteroaryl(C ₁ -C ₄ )alkyl-, wherein any such heteroaryl may be optionally substituted with one or more groups selected from (C ₁ -C ₃ )alkyl, (C ₁ -C ₆ )haloalkyl;

J is H.

In another preferred embodiment, the invention relates to a compound of formula Ic, wherein

Z is aryl, preferably phenyl, wherein each of said aryl is further optionally substituted with one or more fluorines;

R1 is H;

R2 is selected from the group consisting of

heteroaryl(C ₁ -C ₄ )alkyl-, which is (pyridinyl)methyl, (pyridazyl)methyl, (oxadiazolyl)ethyl, (pyrimidinyl)ethyl,

each of said heteroarylalkyl is further optionally substituted with one or more groups selected from methyl and trifluoromethyl;

J is H;

According to preferred embodiments, the invention relates to at least one of the compounds listed in Table 7 below and pharmaceutically acceptable salts thereof.

Table 7: List of preferred compounds having formula (Ic) Example No. Structure Chemical name Example 39 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridin-4-amine Example 40 6-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pteridin-4-amine Example 41 (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pteridin-4-amine Example 42 6-(4-Fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pteridin-4-amine

Compounds of formula (I), including all of the above compounds, can be prepared by the methods shown in the schemes below using known methods.

Scheme 1

In one embodiment of the present invention, compound (Ia) can be prepared according to SCHEME 1 from intermediate compounds (II).

Intermediates (III) can be prepared from intermediate (IIa) by a deoxyamination reaction mediated by reagents such as PyBOP or similar, in the presence of a suitable amine (Reag. 1) or, alternatively, intermediate (IIb) via reaction with a suitable amine (Reag. 1).

Compound (Ia) can be prepared from intermediate (III) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or similar, with a suitable reagent (Reag. 2), such as, for example, organoboron reagents.

In another embodiment of the present invention, intermediate (IV) can be prepared from intermediates (IIa) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or the like with a suitable reagent (Reagent 2), such as, for example, organoboron reagents.

Compound (Ia) can be prepared from intermediate (IV) by a deoxyamination reaction mediated by reagents such as PyBOP or similar, in the presence of a suitable amine (Reag. 1).

Intermediates (IVa) can be prepared from intermediate (IV) using a suitable chlorinating agent such as, for example, phosphorus(V) oxychloride or thionyl chloride.

Compounds (Ia) can be prepared from intermediate (IVa) by amination reaction with a suitable amine (Reagent 1) in the presence of a base such as, for example, DIPEA.

Scheme 2

In another embodiment of the present invention, compound (Ia) can be prepared according to SCHEME 2 from intermediate compound (V).

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

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

Compound (Ia) can be prepared from intermediate (VII) by metal-catalyzed cross-coupling reactions such as Stille or Suzuki or similar with a suitable reagent (Reag. 2) such as, for example, organoboron reagents.

Scheme 3

In one embodiment of the present invention, compound (Ib) can be prepared according to SCHEME 3 from intermediate compound (VIII).

Intermediate (IX) can be prepared from intermediate (VIII) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or similar, with a suitable reagent (Reag. 2), such as, for example, organoboron reagents.

Compounds (Ib) can be prepared from intermediate (IX) by a deoxyamination reaction mediated by reagents like PyBOP or similar, in the presence of a suitable amine (Reag. 1).

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

Compound (Ib) can be prepared from intermediate (X) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or the like with a suitable reagent (Reag. 2) such as, for example, organoboron reagents.

Scheme 4

In one embodiment of the present invention, compound (Ib) can be prepared according to SCHEME 4 from intermediate compound (IX).

Intermediates (XII) can be prepared from intermediate (XI) by a deoxyamination reaction mediated by reagents like PyBOP or similar, in the presence of a suitable amine (Reag. 1).

Compound (Ib) can be prepared from intermediate (XII) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or the like with a suitable reagent (Reag. 2) such as, for example, organoboron reagents.

Scheme 5

In one embodiment of the present invention, compound (Ic) can be prepared according to SCHEME 5 from intermediate compound (XIII).

Intermediate (XIV) can be prepared from intermediate (XIII) via a ring-forming reaction mediated by suitable reagents such as, for example, triethyl orthoformate.

Intermediate (XV) can be prepared from intermediate (XIV) via metal catalyzed cross-coupling reactions such as Stille or Suzuki or similar, with a suitable reagent (Reag. 2), such as, for example, organoboron reagents.

Intermediates (XVI) can be prepared from intermediate (XV) by a deoxyhalosenation reaction mediated by reagents such as thionyl chloride or the like.

Compounds (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.

In a particular aspect, the present invention relates to compounds of formula (IIIa)

(IIIa)

where X is N or CH,

R ₇ is OH and/or Cl;

R ₈ is a halogen.

In a further aspect, the present invention relates to the use of compounds of formula (IIIa) as an intermediate in the preparation of compounds of formula (I), as described above.

It has been unexpectedly found that the compounds of the present invention effectively inhibit the P2X ₃ receptor, and said compounds are useful for the treatment of respiratory diseases.

In one embodiment of the exemplary compounds of formula (I) of the present invention, it has been unexpectedly found that they effectively and selectively inhibit the P2X ₃ receptor, and said compounds are useful for the treatment of respiratory diseases, avoiding adverse effects such as loss of taste.

Compounds of formula (I) are a selective P2X ₃ antagonist, wherein the selective P2X ₃ antagonist is at least 10 times more selective for homomeric P2X ₃ receptor antagonism compared to heteromeric P2X _2/3 receptor antagonism.

In a preferred embodiment, the selective P2X ₃ antagonist is at least 30-fold more selective for homomeric P2X ₃ receptor antagonism compared to heteromeric P2X _2/3 receptor antagonism.

In another preferred embodiment, the selective P2X ₃ antagonist is at least 50-fold more selective for homomeric P2X ₃ receptor antagonism compared to heteromeric P2X _2/3 receptor antagonism.

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

In one aspect, the invention relates to a compound of formula (I) according to the invention for use as a medicament.

In a further aspect, the invention relates to the use of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of disorders associated with the P2X ₃ receptor mechanism, preferably for the treatment of respiratory diseases.

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

More particularly, the invention relates to compounds of formula (I) for use in the prevention and/or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

The invention also relates to a method for the prevention and/or treatment of disorders associated with P2X ₃ receptor mechanisms, wherein said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

In another embodiment, the disorder that can be treated with the compounds of the present invention is selected from the group consisting of cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

In another preferred embodiment, the disorder is selected from cough and chronic cough.

The methods of treatment according to the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, the term "safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or another pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition, but low enough to avoid serious side effects, and yet can be routinely determined by one of skill in the art. The compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered in a single dose or according to a dosage regimen wherein a series of doses are administered at different time intervals over a given period of time. Typical daily dosages can vary depending on the particular route of administration selected.

The invention also relates to pharmaceutical compositions of the compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

The administration of the compounds of the invention and their pharmaceutical compositions can be carried out according to the needs of the patient, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation.

Preferably, the compounds of the present invention are administered orally and by inhalation.

Various solid oral dosage forms can be used to administer the compounds of the invention, including such solid forms as tablets, gelatin capsules, capsules, caplets, granules, lozenges and bulk powders. The compounds of the invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavors, lubricants and the like. Capsules, tablets and sustained release gels are also useful in administering the compounds of the invention.

Preferably, the compounds of the invention are administered in tablet form.

For the administration of the compounds of the present invention, various liquid oral dosage forms can also be used, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms can also contain suitable known inert diluents, such as water, and suitable known excipients, such as preservatives, wetting agents, sweeteners, flavorings, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the invention can be administered, for example, intravenously in the form of an isotonic sterile solution.

For the treatment of respiratory diseases, the compounds of the invention are preferably administered by inhalation.

Inhalation preparations include powders for inhalation, metered-dose aerosols containing a propellant, or inhalation formulations that do not contain a propellant.

For administration in the form of dry powder, single-dose or multi-dose inhalers known from the prior art can be used. In this case, the powder can be placed in gelatin, plastic or other capsules, cartridges or blister packs or in a reservoir.

A diluent or carrier chemically inert with respect to the compounds of the invention, for example lactose or any other additive suitable for improving the respirable fraction, can be added to the powdered compounds of the invention.

Inhalation aerosols containing a propellant such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. Propellant-controlled formulations may also contain other ingredients such as cosolvents, stabilizers and possibly other excipients.

Propellant-free inhalation formulations containing the compounds of the present invention may be in the form of solutions or suspensions in aqueous, alcoholic or aqueous-alcoholic media, and they may be delivered by jet or ultrasonic nebulizers known in the art, or by soft mist nebulizers.

Preferably, the compounds of the present invention are administered orally.

The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

Dosages of the compounds of the invention depend on a variety of factors including, among others, the particular disease being treated, the severity of the symptoms, the route of administration, and the like.

The invention is also directed to a device containing a pharmaceutical composition containing a compound of formula (I) according to the invention, in the form of a single- or multi-dose dry powder inhaler or a metered dose inhaler.

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way. The following examples illustrate the invention.

The examples of testing experiments described herein serve to illustrate the present invention, and the invention is not limited to the examples given.

OBTAINING INTERMEDIATES AND EXAMPLES

Chemical names were generated using Dotmatics software. In some cases, common names of commercially available reagents are used instead of names generated by Dotmatics software.

All reagents, the synthesis of which is not described in the experimental part, are either commercially available, or are known compounds, or can be prepared from known compounds by known methods by a person skilled in the art.

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

Abbreviations - meanings

Et ₂ O: diethyl ether;

Et ₃ N: triethylamine;

TEA: triethylamine;

DCC: N,N'-dicyclohexylcarbodiimide;

PyBOP: (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate;

DMF: dimethylformamide;

EtOAc: ethyl acetate;

RT: room temperature;

THF: tetrahydrofuran;

DCM: dichloromethane;

MeOH: methyl alcohol;

EtOH: ethyl alcohol;

TFA: trifluoroacetic acid;

LC-MS: liquid chromatography/mass spectrometry;

HPLC: high pressure liquid chromatography;

MPLC: medium pressure liquid chromatography;

SFC: supercritical fluid chromatography;

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

DIEA or DIPEA: N,N-diisopropylethylamine;

MeCN: acetonitrile;

MTBE: methyl tert-butyl ether;

TBDMSCl: tert-butyl(chloro)dimethylsilane;

DMSO: dimethyl sulfoxide;

Boc ₂ O: di-tert-butyl dicarbonate;

UPLC: Ultra Performance Liquid Chromatography

General details of the experiment and methods

Analytical methods

Liquid chromatography mass spectrometry

Method 1

UPLC-MS was performed on a Waters Acquity I-Class with a Waters Diode Array Detector coupled to a Waters SQD2 single quadrupole mass spectrometer using a Waters HSS C18 column (1.8 μm, 100×2.1 mm) that was initially incubated at 5% acetonitrile/water (with 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).

Method 2

UPLC-MS was performed on a Waters Acquity I-Class with a Waters Diode Array Detector coupled to a Waters SQD2 single quadrupole mass spectrometer using a Waters BEH Shield RP18 column (1.7 μm, 100×2.1 mm) that was initially incubated at 5% acetonitrile/water (with 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).

Method 3

UPLC-MS was performed on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7 µm 100×2.1 mm (Plus guard cartridge) held at column temperature, which was initially held at 5% acetonitrile/water (with 10 mM 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).

Method 4

UPLC-MS was performed on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7 µm 100×2.1 mm (Plus guard cartridge) held at column temperature, which was initially held at 5% Acetonitrile (Far UV grade) with 0.1% (v/v) formic acid/water (high purity via PureLab Option device) with 0.1% formic acid 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).

Method 4.1

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

Gradient:

Gradient-time flow (ml/min) %A %IN 0,00 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

Definition-MS, UV FDM

MS ionization method - electrospray (positive/negative ion).

Method 4.2

Acquity UPLC - QDa mass spectrometer with a C18 reversed phase column (50×2.1 mm Acquity CSH with 1.7 μm particle size), maintained at 40°C, eluting A: 95/5 water/acetonitrile+0.05% formic acid; B: 95/5 acetonitrile/water+0.05% conc. ammonia.

Gradient:

Gradient-time flow (ml/min) %A %IN 0,00 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

Definition-MS, UV FDM

MS ionization method - electrospray (positive/negative ion).

NMR

¹ H nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker or Varian instrument operating at 400 MHz using the specified solvent at about room temperature unless otherwise stated. In all cases, NMR data are consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using the conventional abbreviations for major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; sh, broad.

Preparative reversed-phase HPLC conditions

Preparative HPLC cleanup is performed by reversed-phase HPLC using a Waters Fractionlynx Preparative HPLC System (2525 pump, 2996/2998 UV/VIS detector, 2767 Liquid Handler) or an equivalent HPLC system such as the Gilson Trilution UV Targeted System. The Waters 2767 Liquid Handler functions as both an autosampler and a fraction collector. Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl, 10 μm, 19 x 150 mm, or a Waters CSH Phenyl Hexyl, 19 x 150, 5 μm column are used for preparative cleanup of compounds. Appropriate focused gradients are chosen based on acetonitrile and methanol solvent systems under acidic or basic conditions. Modifiers used under acidic/basic conditions are formic acid or trifluoroacetic acid (0.1% v/v) and ammonium bicarbonate (10 mM), respectively. Cleanup is monitored using Waters Fractionlynx software via monitoring at 210-400 nm and triggering at a collection threshold of 260 nm and, when using Fractionlynx, the presence of the target molecular ion observed under API conditions. Collected fractions are analyzed by LCMS (Waters Acquity systems with Waters SQD).

Chiral supercritical fluid chromatography (SFC) separation protocol

Diastereomeric separation of compounds was performed by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with multi-level injector module). The Waters 2767 liquid handler acts as both an autosampler and a fraction collector. The appropriate isocratic methods were chosen based on methanol, ethanol or isopropanol solvent systems under unmodified or basic conditions. The standard SFC method used was modifier, CO2, 100 ml/min, 120 bar backpressure, column temperature 40°C. The modifier used under basic conditions was diethylamine (0.1% v/v). The modifier used under acidic conditions is formic acid (0.1% v/v) or trifluoroacetic acid (0.1% v/v). SFC cleanup is controlled by Waters Fractionlynx software via monitoring at 210-400 nm and triggering at a collection threshold, typically 260 nm. Collected fractions are analyzed by SFC (Waters/Thar SFC systems with Waters SQD). Fractions containing the desired product are concentrated by vacuum centrifugation.

Supercritical fluid chromatography - mass spectrometry, analytical conditions

Method 5

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with 15% methanol/ _CO2 (m 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 6

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with 20% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 7

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 55% ethanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 8

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 20% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 9

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 30% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 10

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 50% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 11

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 25% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 12

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 15% ethanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 13

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 25% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 14

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 35% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 15

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 55% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 16

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 15% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 17

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 20% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 18

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-C column with 15% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 19

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-C column with 15% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 20

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-C column with 25% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 21

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-SC column with 55% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 22

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with 10% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 23

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with 30% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 24

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 20% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 25

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 40% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 26

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 55% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 27

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with 55% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 28

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 20% ethanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 29

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 25% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 30

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 55% methanol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 31

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with 30% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

Method 32

SLC-MS was performed on Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-C column with 40% isopropyl alcohol/ _CO2 (with 0.1% diethylamine) running isocratically at 5 mL/min, 120 bar backpressure, 40°C column temperature.

OBTAINING INTERMEDIATES AND EXAMPLES

Intermediate connection 1

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

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 for 20 h. The mixture was cooled to 40 °C and water (100 ml) was added. The mixture was stirred for 30 min, then more water (300 ml) was added. The reaction mixture was filtered and the solid was washed with water (3 x 100 ml), a solution of 10% methanol in diethyl ether (3 x 100 ml), and diethyl ether (3 x 100 ml) to give the title compound (33.0 g, 90% yield) as a light brown solid.

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

Intermediate connection 2

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

Nitrogen was bubbled through a mixture of 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 N,N-dimethylformamide (10 ml) and water (2 ml) for 5 min, then tetrakis(triphenylphosphine)palladium(0) (664 mg, 0.57 mmol) was added. The resulting mixture was heated to 95 °C for 16 h. After returning to room temperature, the reaction mixture was 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.

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

The following compound was synthesized according to the procedure described for the preparation of 6-(4-Fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one:

Intermediate connection No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Intermediate connection 19 6-Phenylpyrido[2,3-d]pyrimidin-4(3H)-one
LCMS (Method 4): [MH+]=224 at 3.12 min.

Example 1

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

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) were added in turn (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.17 g, 2.25 mmol) and diisopropylethylamine (1.7 ml, 9.63 mmol). The resulting mixture was heated to 45 °C for 45 min, then 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (600 mg, 3.0 mmol) was added and heating was maintained at 45 °C for 16 h. 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 x 20 mL), passed through a hydrophobic frit, and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (190 mg, 25%).

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

Intermediate connection 20

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

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

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 portionwise and the reaction mixture was stirred for 30 min. (2-Chloromethoxyethyl)trimethylsilane (8.2 mL, 46.45 mmol) was then added dropwise. The reaction mixture was then stirred at 0 °C for 1 h and then allowed to warm 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 x 50 mL). The combined organic phases were dried over _MgSO4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 0-70% ethyl acetate in dichloromethane to give the title compound (6.0 g, 54%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.01 (d, J=2.4 Hz, 1 H), 8.74 (d, J=2.4 Hz, 1 H), 8.40 (s, 1 H), 5.52 (s, 2 H), 3.66-3.62 (m, 2 H), 0.98-0.95 (m, 2 H), 0.02 (s, 9 H).

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

Nitrogen was bubbled through a suspension 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), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (401 mg, 0.49 mmol), potassium acetate (1928 mg, 19.65 mmol) in 1,4-dioxane (80 mL) for 5 min. The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature. To the resulting suspension were added 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 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (22 mg, 0.027 mmol). The reaction mixture was heated to 100 °C for another 2 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 30-50% ethyl acetate in dichloromethane. The resulting residue was triturated with diethyl ether to give the title compound (2400 mg, 65%) as a pale yellow solid.

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

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

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 h. The solvent was removed in vacuo and the residue was quenched with saturated sodium bicarbonate solution and water. The solid was filtered and dried under reduced pressure to give the title compound (458 mg, 70%) as a yellow solid.

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

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

Intermediate connection No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Intermediate connection 21 6-(5-methylpyrimidin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
LCMS (Method 3): [MH+]=269 at 2.76 min. Intermediate connection 22 6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
LCMS (Method 3): [MH+]=239 at 2.55 min. Intermediate connection 23 6-(5-fluoropyridin-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
LCMS (Method 4): [MH+]=272 at 3.02 min.

Example 49

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

6-(5-Methylthiazol-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 phosphorus(V) oxychloride (0.027 ml, 0.30 mmol) was added. The reaction mixture was heated at 95°C for 2 h and cooled to room temperature. The solvent was removed in vacuo. To the resulting residue were added [3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methanamine 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 h. The reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite®. The solvent was removed in vacuo. The resulting residue was purified by preparative HPLC to give the title compound (3.1 mg, 3%) as a pale yellow solid.

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

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

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 50 6-(5-methylthiazol-2-yl)-N-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.55 (t, J=5.1 Hz, 1 H), 9.50 (d, J=2.4 Hz, 1 H), 9.20 (d, J=2.4 Hz, 1 H), 9.15 (s, 2 H), 8.66 (s, 1 H), 7.76-7.75 (m, 1 H), 4.95 (d, J=4.7 Hz, 2 H), 2.57 (d, J=1.1 Hz, 3 H). LCMS (Method 4): [MH+]=404 at 3.26 min. Example 51 N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.73 (br s, 1 H), 9.54 (d, J=2.4 Hz, 1 H), 9.25 (d, J=2.4 Hz, 1 H), 8.65 (s, 1 H), 7.77 (d, J=1.2 Hz, 1 H), 5.05 (d, J=3.3 Hz, 2 H), 2.58 (d, J=1.2 Hz, 3 H), 2.32 (s, 3 H). LCMS (Method 4): [MH ⁺ ]=340 at 2.63 min. Example 52 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.67-9.65 (m, 1 H), 9.55 (d, J=2.4 Hz, 1 H), 9.30-9.28 (m, 1 H), 8.65 (s, 1 H), 7.80-7.79 (m, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.55 (d, J=8.8 Hz, 1 H), 5.10-5.09 (m, 2 H), 2.64 (s, 3 H), 2.59 (s, 3 H). LCMS (Method 4): [MH ⁺ ]=350 at 2.35 min.

Intermediate connection 24

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

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

Phosphorus oxychloride (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 for 2 h, after which LC-MS analysis showed conversion to the desired product. The solvents were removed in vacuo and the resulting residue was partitioned between DCM (40 mL) and saturated aqueous NaHCO ₃ (10 mL). The layers were mixed thoroughly before separation, and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were washed with saturated aqueous _NaHCO3 (10 ml) and then water (10 ml) before drying through a phase separation frit. The solvents were removed in vacuo to give a dark brown semi-solid which was used directly in the next step without further purification (1.6 g, >100%).

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

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 and purified by preparative HPLC to give the title compound (61 mg, 29%) as a colorless solid.

¹ H NMR (400 MHz, DMSO): δ 11.76-11.75 (m, 1 H), 9.42 (d, J=2.5 Hz, 1 H), 9.22 (d, J=2.5 Hz, 1 H), 8.83 (d, J=6.8 Hz, 1 H), 8.65 (s, 1 H), 8.03 (ddd, J=3.2, 5.4, 12.0 Hz, 2 H), 7.50 (dd, J=8.8, 8.8 Hz, 2 H), 7.40 (dd, J=8.0, 8.0 Hz, 1 H), 6.28-6.21 (m, 2 H), 5.38 (dd, J=6.9, 6.9 Hz, 1 H), 1.65 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH+]=362 at 2.85 min.

The following compounds were synthesized according to the procedure described for the preparation of 6-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2(1H)-one using the appropriate amine reagent:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 54 2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(5-methyl-1,2,4-oxadiazol-3-yl)ethan-1-ol
¹ H NMR (400 MHz, DMSO): δ 9.42 (s, 1 H), 9.22 (s, 1 H), 9.13 (d, J=7.0 Hz, 1 H), 8.64 (s, 1 H), 8.00 (dd, J=6.3, 6.3 Hz, 2 H), 7.45 (dd, J=8.5, 8.5 Hz, 2 H), 5.83-5.76 (m, 1 H), 5.45 (dd, J=5.4, 5.4 Hz, 1 H), 4.07 (dd, J=5.5, 5.5 Hz, 2 H), 2.34 (s, 3 H). LCMS (Method 4): [MH+]=367 at 3.23 min. Example 55 (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.30 (d, J=2.4 Hz, 1 H), 9.04 (d, J=2.4 Hz, 1 H), 8.59 (s, 1 H), 7.88 (dd, J=5.5, 8.6 Hz, 2 H), 7.37 (dd, J=8.8, 8.8 Hz, 2 H), 5.79 (q, J=7.0 Hz, 1 H), 2.43 (s, 3 H), 1.70 (d, J=7.0 Hz, 3 H). NH not observed. LCMS (Method 4): [MH+]=351 at 2.83 min. Chiral analysis (Method 26) at 1.69 min. Example 56 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.40 (d, J=2.5 Hz, 1 H), 9.19-9.13 (m, 2 H), 8.69 (s, 1 H), 7.97 (ddd, J=3.1, 5.3, 12.0 Hz, 2 H), 7.45 (dd, J=8.9, 8.9 Hz, 2 H), 6.01-5.95 (m, 1 H), 2.67 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH+]=367 at 3.07 min. Example 58 (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (d, J=2.63 Hz, 1 H), 9.12 (d, J=2.19 Hz, 1 H), 8.96 (d, J=7.89 Hz, 1 H), 8.59 (s, 1 H), 7.93 (dd, J=8.55, 5.48 Hz, 2 H), 7.39 (t, J=8.77 Hz, 2 H), 5.68-5.76 (m, 1 H), 2.53 (s, 3 H), 1.64 (d, J=7.02 Hz, 3 H). LCMS (Method 4.1): [MH+]=351.1 at 0.66 min Example 59 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (d, J=2.19 Hz, 1 H), 9.21 (d, J=2.19 Hz, 1 H), 8.79 (s, 1 H), 8.41 (s, 1 H), 7.95-8.02 (m, 2 H), 7.40-7.50 (m, 2 H), 2.31 (s, 3 H), 1.88 (s, 6 H). LCMS (Method 4.1): [MH+]=365.1 at 0.75 min Example 60 N-(1-(3,5-difluoropyridin-2-yl)ethyl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (d, J=2.19 Hz, 1 H), 9.19 (d, J=2.41 Hz, 1 H), 8.93 (bd, J=7.23 Hz, 1 H), 8.50 (s, 1 H), 8.42 (d, J=2.41 Hz, 1 H), 7.86-7.97 (m, 3 H), 7.39 (t, J=8.77 Hz, 2 H), 5.83 (sq, J=7.00 Hz, 1 H), 1.60 (d, J=7.02 Hz, 3 H). LCMS (Method 4.1): [MH+]=389.1 at 0.79 min Example 63 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (d, J=2.41 Hz, 1 H), 8.92 (d, J=2.41 Hz, 1 H), 8.85 (st, J=5.37 Hz, 1 H), 8.59 (s, 1 H), 7.88 (dd, J=8.66, 5.37 Hz, 2 H), 7.39 (t, J=8.77 Hz, 2 H), 3.90-3.99 (m, 2 H), 3.24-3.32 (m, 2 H), 2.26 (s, 3 H). LCMS (Method 4.1): [MH+]=351.0 at 0.58 min Example 63a N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.36 (d, J=2.4 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 9.00-8.98 (m, 1 H), 8.57 (s, 1 H), 8.47 (d, J=2.4 Hz, 1 H), 8.00-7.92 (m, 3 H), 7.47-7.41 (m, 2 H), 5.90-5.84 (m, 1 H), 1.65 (d, J=6.8 Hz, 3 H). LCMS (Method 4): [MH+]=382 at 4.3 min.

Example 2

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

6-(4-Fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (intermediate 2) (23.5 g, 97.4 mmol, 1 equiv) was suspended in _SOCl2 (240 mL) then DMF (2.5 mL) was added dropwise. The reaction mixture was heated to reflux until a clear solution was obtained. The reaction was then terminated and the volatiles were removed under reduced pressure. The residue was soaked with EtOAc then filtered and dried to give 4-chloro-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine (23.6 g, 91.9 mmol, 94% yield).

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 semisaturated aqueous NaCl solution and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by DP chromatography (Biotage Isolera, 28 g NH cartridge, gradient elution from 0 to 60% AcOEt in dichloromethane) followed by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 0 to 35% B in A. A: water/acetonitrile 95:5+0.05% HCOOH, B: acetonitrile/water 95:5+0.05% HCOOH) to afford (R)-5-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide (122 mg, 0.284 mmol, 73.8% yield) as an off-white powder.

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

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

The following examples are synthesised by adaptations of this technique.

Example No. Chemical name, structure Analytical data, 1H NMR, LC-MS Example 3 (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
LCMS (Method 4.1): 0.60 min, 361.2 [M+H]+.
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (d, J=1.75 Hz, 1 H) 9.22 (d, J=1.75 Hz, 1 H) 9.02 (bd, J=7.23 Hz, 1 H) 8.54 (s, 1 H) 7.98 (dd, J=8.22, 5.59 Hz, 2 H) 7.64 (d, J=8.77 Hz, 1 H) 7.50 (d, J=8.65 Hz, 1 H) 7.43 (t, J=8.66 Hz, 2 H) 5.76 (quin, J=7.02 Hz, 1 H) 2.58 (s, 3 H) 1.71 (d, J=7.02 Hz, 3 H). Example 4 (S)-2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(6-methoxypyridin-3-yl)ethan-1-ol
LCMS (Method 4.1): 0.63 min, 392.2 [M+H]+,
¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.30 (s, 1 H) 9.14 (s, 1 H) 8.78-9.46 (m, 1 H) 8.76 (shd, J=7.67 Hz, 1 H) 8.54 (d, J=0.88 Hz, 1 H) 8.23 (shs, 1 H) 7.93 (dd, J=7.34, 5.37 Hz, 2 H) 7.77 (shd, J=8.55 Hz, 1 H) 7.40 (t, J=8.12 Hz, 2 H) 6.76 (d, J=8.55 Hz, 1 H) 5.48 (kv, J=6.94 Hz, 1 H) 5.10 (t, J=5.48 Hz, 1 H) 3.78 (d, J=1.38 Hz, 5 H) Example 5 6-(4-fluorophenyl)-N-(2-morpholinoethyl)pyrido[2,3-d]pyrimidin-4-amine formate
LCMS (Method 4.1): 0.34 min, 354.1 [M+H]+,
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (d, J=2.41 Hz, 1 H) 8.95 (d, J=2.41 Hz, 1 H) 8.62 (st, J=4.82 Hz, 1 H) 8.57 (s, 1 H) 7.86-7.92 (m, 2 H) 7.39 (t, J=8.88 Hz, 2 H) 3.61-3.76 (m, 2 H) 3.51-3.57 (m, 4 H) 2.58 (t, J=6.91 Hz, 2 H) 2.39-2.45 (m, 4 H).

Intermediate 3 - Procedure A

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

To a mixture of 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (Intermediate 1) (1.0 g, 4.42 mmol) and 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (996 mg, 4.98 mmol) in N,N-dimethylformamide (25 ml) were added N,N-diisopropylethylamine (3.9 ml, 22.12 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.76 g, 5.31 mmol) and the mixture was heated to 40 °C for 5 h and 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 x 40 ml). The organic phases were combined, washed with brine (50 ml), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with 0-10% methanol in dichloromethane. The product containing fractions were combined and triturated with diethyl ether to give the title compound (766 mg, 46% yield) as a white solid.

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

Intermediate 4 - Procedure B

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

A mixture of 6-bromo-4-chloropyrido[2,3-d]pyrimidine (1 g, 4.09 mmol), (6-methylpyridin-3-yl)methanamine (0.500 g, 4.09 mmol) and triethylamine (3 ml, 21.52 mmol) in 1,4-dioxane/DMF 5:1 (Volume: 12 ml) was stirred at 100°C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (Biotage Isolera, 55 g NH cartridge, gradient elution from 0 to 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 both in the fractions and in the upper part of the cartridge as an insoluble residue.

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

The following intermediates are synthesized via adaptations of Method A or B (see table for specific method) by reacting with an appropriate substrate and an amine intermediate.

Intermediate connection No. Chemical name, structure Analytical data Source material - Methodology Intermediate connection 5 6-Bromo-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.40-9.39 (m, 1 H), 9.15 (d, J=6.1 Hz, 2 H), 8.66 (s, 1 H), 7.64 (d, J=8.6 Hz, 1 H), 7.55 (d, J=8.6 Hz, 1 H), 5.06 (d, J=5.6 Hz, 2 H), 2.65 (s, 3 H). 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one, (Intermediate 1), Method A Intermediate connection 6 (R)-6-Bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]-pyrimidin-4-amine
LCMS (Method 4): [MH+]=399.0 and 401.0 at 3.43 min. 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one, (Intermediate 1), Method A

Example 6

N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]-pyrimidin-4-amine

Nitrogen was bubbled through a solution of 5-methyl-2-(tributylstannyl)thiazole (902 mg, 2.67 mmol), 6-bromo-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (Intermediate 3) (2.75 mg, 0.82 mmol) in N,N-dimethylformamide (12 ml) for 5 min, then tetrakis(triphenylphosphine)palladium(0) (142 mg, 0.123 mmol) was added. The resulting mixture was heated to 95 °C for 18 h. After returning to room temperature, the reaction mixture was diluted with water (60 ml) and brine (25 ml) and extracted with ethyl acetate (3×30 ml). The combined organic phases were filtered through a Celite® cartridge, washed with water (50 mL), dried over MgSO ₄ and filtered. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% methanol in dichloromethane to give the title compound (140 mg, 48% yield) as an off-white solid.

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

The following compounds are synthesized according to the procedure described for the preparation of N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine using the appropriate stannane reagent and starting from the intermediate shown in the table.

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Initial intermediate compound Example 7 N-((6-Methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.61 (d, J = 2.0 Hz, 1 H), 8.97 (d, J = 2.0 Hz, 1 H), 8.82 (s, 1 H), 8.52 (s, 1 H), 8.09 (dd, J = 5.4, 5.4 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.3 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H), 5.13 (d, J = 4.5 Hz, 2 H), 2.74 (s, 3 H), 2.41 (s, 3 H). LCMS (Method 3): [MH+]=344 at 2.84 min. Intermediate connection 5 Example 8 6-(5-Chloropyridin-2-yl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.51 (d, J=2.3 Hz, 1 H), 9.32 (t, J=5.6 Hz, 1 H), 9.27 (d, J=1.8 Hz, 1 H), 8.62 (d, J=1.3 Hz, 1 H), 8.42 (s, 1 H), 8.05-7.99 (m, 2 H), 7.41 (d, J=8.6 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 4.86 (d, J=4.8 Hz, 2 H), 2.40 (s, 3 H). LCMS (Method 3): [MH+]=364 at 3.10 min. Intermediate connection 5 Example 9 (R)-6-(5-Methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.71 (s, 1 H), 9.52-9.48 (m, 1 H), 9.21 (s, 3 H), 8.63 (d, J=12.1 Hz, 2 H), 8.15 (d, J=8.1 Hz, 1 H), 7.87 (d, J=7.8 Hz, 1 H), 5.72-5.70 (m, 1 H), 2.42 (s, 3 H), 1.77 (d, J=6.6 Hz, 3 H). LCMS (Method 3): [MH+]=412 at 3.95 min. Intermediate connection 6 Example 10 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.68 (d, J=2.6 Hz, 1 H), 9.36 (d, J=2.6 Hz, 1 H), 9.29 (t, J=5.7 Hz, 1 H) , 8.63 (s, 1 H), 8.60 (s, 1 H), 8.51 (d, J=1.8 Hz, 1 H), 8.07 (d, J=8.3 Hz, 1 H), 7.82 (dd, J=8.3, 1.8 Hz, 1 H), 7.70 (dd, J=7.9, 2.2 Hz, 1 H), 7, 21 (d, J=7.9 Hz, 1 H), 4.79 (d, J=5.7 Hz, 2 H), 2.44 (s, 3 H), 2.38 (s, 3H). LCMS: (Method 4.1): 0.33 min, 342.9 m/z [M+H]+. Intermediate connection 4 Example 107 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.47 (d, J=2.4 Hz, 1 H), 9.32 (d, J=2.4 Hz, 1 H), 9.25-9.23 (m, 1 H), (s, 2 H), 8.59 (s, 1 H), 7.79-7.76 (m, 1 H), 5.69-5.67 (m, 1 H), 2.58 (s, 3 H), 1.73 (d, J=7.1 Hz, 3 H). LCMS (Method 3): [MH+]=418 at 4.29 min. Chiral analysis (Method 27) at 3.38 min. Intermediate connection 6

Intermediate connection 7

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

Nitrogen was bubbled through a solution of 6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (Intermediate 1) (832 mg, 3.68 mmol), 5-chloro-2-(tributylstannyl)thiazole (2.0 g, 4.97 mmol) in N,N-dimethylformamide (35 ml) for 5 min. Tetrakis(triphenylphosphine)palladium(0) (638 mg, 0.552 mmol) was added and the mixture was heated to 95°C for 18 h. After returning to room temperature, the reaction mixture was filtered and the solid was washed with N,N-dimethylformamide (50 mL) then 10% methanol in dichloromethane (3 x 25 mL) to give the title compound (470 mg, 49%) as an off-white solid.

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

Example 11

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

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) were added (6-methylpyridazin-3-yl)methanamine dihydrochloride (69 mg, 0.35 mmol), N,N-diisopropylethylamine (0.27 ml, 1.55 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.93 mg, 0.37 mmol). The resulting mixture was heated to 60°C for 48 h. After returning to room temperature, the reaction mixture was 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 x 15 ml). The organic phases were combined, passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (9.5 mg, 7%) as an off-white solid.

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

The following compounds were synthesized according to the procedure described for the preparation of (R)-6-(5-chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine using the appropriate amine reagent:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 12 6-(5-Chloropyridin-2-yl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.66 (d, J=2.3 Hz, 1 H), 9.44 (d, J=2.0 Hz, 1 H), 9.28 (d, J=6.8 Hz, 1 H), 8.75 (d, J=2.0 Hz, 1 H), 8.58 (s, 1 H), 8.18 (d, J=8.3 Hz, 1 H), 8.12 (dd, J=2.4, 8.5 Hz, 1 H), 5.78-5.72 (m, 1 H), 2.25 (s, 3 H), 1.68 (d, J=7.1 Hz, 3 H). LCMS (Method 3): [MH+]=368 at 3.87 min.

Example 13

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

Nitrogen was bubbled through a mixture of (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]dichloropalladium(II) (18 mg, 0.0251 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) for 10 min. The reaction mixture was heated to 110 °C for 20 min in the microwave. After returning to room temperature, water (2 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were dried over _MgSO4 , filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with 0-20% methanol in dichloromethane, then preparative HPLC to give the title compound (37 mg, 35%) as an off-white solid.

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

Compound 18 is obtained as a by-product in the preparation of Example 17.

The following intermediates were synthesized via adaptations of this procedure, starting from suitable intermediates:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Initial intermediate compound Example 14 N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine
LCMS (Method 4.1): 0.38 min, 342.0 m/z [M+H]+, CSH 2 min, ¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.34 (d, J=2.2 Hz, 1 H), 9.12-9.21 (shs, 1 H), 9.03 (d, J=2.6 Hz, 1 H), 8.60 (s, 1 H), 8.51 (d, J=1.8 Hz, 1 H), 7.79 (d, J=8.3 Hz, 2 H), 7.66-7.73 (m, 1 H), 7.37 (d, J=8.3 Hz, 2 H), 7.21 (d, J=7.9 Hz, 1 H), 4.79 (shs, 2 H), 2.43 (s, 3 H), 2.38 (s, 3 H). Intermediate connection 4 Example 15 N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidin-4-amine
LCMS (Method 4.1): 0.42 min, m/z 347.9 [M+H]+, CSH 2 min, ¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.21-9.35 (m, 1 H), 9.10-9.20 (t, 1 H), 8.85 (d, J=2.63 Hz, 1 H), 8.57 (s, 1 H), 8.45-8.53 (m, 1 H), 7.62-7.74 (m, 1 H), 7.48-7.62 (m, 1 H), 7.21 (d, J=7.89 Hz, 1 H), 6.83-6.98 (m, 1 H), 4.78 (d, J=5.70 Hz, 2 H), 2.52 (s, 3 H), 2.44 (s, 3 H). Intermediate connection 4 Example 16 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
LCMS (Method 4.2): 0.39 min, m/z 345.9 [M+1]+, ¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.34 (d, J=2.19 Hz, 1 H), 9.15 (t, J=1.00 Hz, 1 H), 9.04 (d, J=2.19 Hz, 1 H), 8.62 (s, 1 H), 8.51 (d, J=1.75 Hz, 1 H), 7.93 (dd, J=8.77, 5.26 Hz, 2 H), 7.69 (bd, J=2.19 Hz, 1 H), 7.41 (t, J=8.77 Hz, 2 H), 7.21 (d, J=7.89 Hz, 1 H), 4.79 (d, J=5.26 Hz, 2 H), 2.44 (s, 3 H). Intermediate connection 4 Example 17 2-(4-(((6-methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzonitrile
LCMS (Method 4.1): 0.33 min, m/z 352.9 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.15-9.20 (m, 2 H), 9.02 (d, J=2.2 Hz, 1 H), 8.68 (s, 1 H), 8.49 (d, J=2.2 Hz, 1 H), 8.01-8.10 (m, 1 H), 7.89 (d, J=0.9 Hz, 1 H), 7.82 (s, 1 H), 7.68 (d, J=7.9 Hz, 2 H), 7.20 (d, J=7.9 Hz, 1 H), 4.78 (d, J=5.3 Hz, 2 H), 2.43 (s, 3 H). Intermediate connection 4 Example 18 2-(4-(((6-methylpyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-6-yl)benzamide
LCMS (Method 4.1): 0.14 min (solvent front) and 0.28 min, m/z 371.0 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ ppm. 9.11-9.21 (shs, 1 H), 8.92 (d, J=2.6 Hz, 1 H), 8.78 (d, J=2.2 Hz, 1 H), 8.62 (s, 1 H), 8.49 (d, J=1.8 Hz, 1 H), 7.78 (shs, 1 H), 7.68 (dd, J=7.9, 2.2 Hz, 1 H), 7.56-7.65 (m, 4 H), 7.41 (shs, 1 H), 7.20 (d, J=7.9 Hz, 1 H), 4.76 (shs, 2 H), 2.43 (s, 3 H). Intermediate connection 4

Example 19

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

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)methanamine hydrochloride (73.9 mg, 0.409 mmol) in DMF (volume: 2 ml). Stirring was continued for 6 h at 80°C. After the conversion of the starting materials to 6-bromo-N-((3,5-difluoropyridin-2-yl)methyl)pyrido[2,3-d]pyrimidin-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)Cl ₂ ⋅CH ₂ Cl ₂ (33.4 mg, 0.041 mmol). Stirring was continued for 16 h at 80 °C. The mixture was cooled to rt, then formic acid (0.154 mL, 4.09 mmol) was added. Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, 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 in 15 CV) gave 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 an off-white powder.

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

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.29-9.47 (m, 1 H), 9.20 (t, 1 H), 9.10 (d, J=2.41 Hz, 1 H), 8.54-8.63 (m, 1 H), 8.38-8.49 (m, 1 H), 7.81-8.04 (m, 3 H), 7.42 (t, J=8.88 Hz, 2 H), 4.93-5.03 (m, 2 H).

The following examples are synthesized by adaptations of this procedure using appropriate amines and boronic acids or esters, and starting from 6-bromo-4-chloropyrido[2,3-d]pyrimidine.

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 20 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
LCMS (Method 4.1): 0.53 min, m/z 346.7 [M+H]+,
¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.34-9.40 (m, 2 H), 9.10 (d, J=2.6 Hz, 1 H), 8.59 (s, 1 H), 7.85-8.01 (m, 2 H), 7.47-7.65 (m, 2 H), 7.42 (t, J=9.0 Hz, 2 H), 5.05 (d, J=4.8 Hz, 2 H), 2.59 (s, 3 H).

Intermediate connection 8

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

2-Amino-5-bromo-pyridine-3-carboxylic acid (3 g, 13.82 mmol) was finely ground with urea (4.90 g, 81.59 mmol). The mixture was heated to the evaporation temperature of urea (280 °C) using a sand bath until solidification. After cooling, the resulting solid was dissolved in 50 mL of 2 N sodium hydroxide and then filtered hot. 6 N HCl solution was added dropwise to the mixture until pH 8. The resulting precipitate was filtered, washed with cold water and dried in vacuo to give the title compound (3.0 g, 89.5%).

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

Intermediate connection 9

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

To a suspension of 6-bromopyrido[2,3-d]pyrimidine-2,4-diol (Intermediate 8) (500 mg, 2.07 mmol) in POCl ₃ (5 ml, 53.65 mmol) was added N,N-diisopropylethylamine (1.0 ml, 5.74 mmol). The mixture was heated to 120 °C for 18 h. The reaction mixture was poured into ice, diluted with dichloromethane (15 ml) and stirred at room temperature for one hour. The aqueous phase was extracted with dichloromethane (2 x 70 ml). The organic phases were combined, washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ and filtered. The solvent was removed in vacuo to give the title compound (470 mg, 82%) as a red solid.

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

Intermediate connection 10

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

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

To a solution of 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (Intermediate 9) (370 mg, 1.33 mmol) and (6-methylpyridazin-3-yl)methanamine dihydrochloride (312 mg, 1.59 mmol) in tert-butanol (10 ml) was added N,N-diisopropylethylamine (0.69 ml, 3.98 mmol). The reaction mixture was heated to 40 °C for one hour. The solvent was removed in vacuo and the residue was taken to the next step without further purification.

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

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)ethan-1-one (Intermediate 10)

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 for one 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 MgSO ₄ , filtered and the solvent was removed in vacuo to give the title compound (350 mg, 58%) as a red solid.

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

Example 21 and 22

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 (Ex. 21) and 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (Ex. 22)

1-(4-(6-Bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-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]dichloropalladium(II) (8 mg, 0.01 mmol) were placed in a microwave tube. 1,4-Dioxane (2 ml) and water (0.5 ml) were added and the solution was degassed with nitrogen for 10 min. The reaction mixture was heated to 110 °C for 20 min in the microwave reactor. After returning to room temperature, water (2 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic phase was combined, dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound.

Example 21 (18 mg, 35%)

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.00 (d, J=2.5 Hz, 1 H), 8.14 (d, J=2.5 Hz, 1 H), 7.61- 7.56 (m, 3 H), 7.47 (d, J=8.5 Hz, 1 H), 7.40 (d, J=8.5 Hz, 1 H), 7.20-7.15 (m, 2 H), 5.03 (d, J=4.4 Hz, 2 H), 4.07 (dd, J=3.7, 5.5 Hz, 2 H), 3.99 (dd, J=3.4, 5.8 Hz, 2 H), 3.71 (dd, J=5.3, 5.3 Hz, 2 H), 3.55 (dd, J=5.2, 5.2 Hz, 2 H), 2.76 (s, 3 H), 2.17 (s, 3 H). LCMS (Method 3): [MH+]=473.0 at 3.4 min.

Example 22 (9.0 mg, 21%)

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

Example 23

1-(4-(4-(((6-Methylpyridazin-3-yl)methyl)amino)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one

Nitrogen was bubbled through a mixture of 1-(4-(6-bromo-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (Intermediate 10) (50 mg, 0.109 mmol), 5-methyl-2-(tri-n-butylstannyl)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 for 18 h. After returning to room temperature, the reaction mixture was diluted with methanol (5 mL) and loaded into an SCX cartridge. The cartridge was washed with methanol and the filtrate was collected, eluting with 7M ammonia in methanol. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (15 mg, 29%) as an off-white solid.

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

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

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 24 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
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.00 (d, J=2.5 Hz, 1 H), 8.14 (d, J=2.5 Hz, 1 H), 7.61- 7.56 (m, 3 H), 7.47 (d, J=8.5 Hz, 1 H), 7.40 (d, J=8.5 Hz, 1 H), 7.20-7.15 (m, 2 H), 5.03 (d, J=4.4 Hz, 2 H), 4.07 (dd, J=3.7, 5.5 Hz, 2 H), 3.99 (dd, J=3.4, 5.8 Hz, 2 H), 3.71 (dd, J=5.3, 5.3 Hz, 2 H), 3.55 (dd, J=5.2, 5.2 Hz, 2 H), 2.76 (s, 3 H), 2.17 (s, 3 H). LCMS (Method 4): [MH+]=470.0 at 2.40 min. Example 25 1-(4-(6-Methyl-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66 (d, J = 1.3 Hz, 1 H), 7.85 (s, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.38 (d, J = 8.3 Hz, 2 H), 5.00 (d, J = 4.3 Hz, 2 H), 4.03 (t, J = 5.2 Hz, 2 H), 3.97 (t, J = 5.0 Hz, 2 H), 3.70 (dd, J = 5.2, 5.2 Hz, 2 H), 3.53 (dd, J = 5.1, 5.1 Hz, 2 H), 2.76 (s, 3 H), 2.41 (s, 3 H), 2.16 (s, 3 H). LCMS (Method 4): [MH+]=393.0 at 1.99 min.

Intermediate connection 25

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

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 h and then cooled to room temperature. The solvent was removed in vacuo. The resulting residue was suspended in dioxane (5.0 mL), and then DIPEA (0.72 mL, 4.15 mmol) and [1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl]amine hydrochloride (236 mg, 1.24 mmol) were added. The reaction mixture was heated at 95 °C for 3 h and then cooled to room temperature. Water was added and the resulting solid was filtered and dried in vacuo. The residue was purified by preparative HPLC to give the title compound (257 mg, 82%) as an off-white solid as a mixture of two enantiomers.

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

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

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 65 6-(5-methylpyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO) δ 9.79-9.73 (m, 2 H), 9.45-9.42 (m, 1 H), 8.64 (s, 2 H), 8.12 (d, J=7.8 Hz, 1 H), 7.88 (d, J=7.4 Hz, 1 H), 5.22 (d, J=4.5 Hz, 2 H), 2.41 (s, 3 H). LCMS (Method 3): [MH ⁺ ]=388 at 3.83 min. Example 66 (6-(5-Fluoro-2-pyridyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.78-9.70 (m, 1 H), 9.50 (s, 1 H), 9.36 (d, J=5.8 Hz, 1 H), 8.82 (s, 1 H), 8.68 (s, 1 H), 8.36-8.26 (m, 1 H), 8.04 (dd, J=9.0, 9.0 Hz, 1 H), 5.85 (dd, J=6.3, 6.3 Hz, 1 H), 2.37 (s, 3 H), 1.79 (d, J=6.4 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=352 at 2.75 min. Chiral analysis (Method 22) at 3.61 min. Example 67 (R)-6-(5-fluoropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.68 (s, 1 H), 9.47 (s, 1 H), 9.21 (s, 2 H), 9.14 (d, J=6.4 Hz, 1 H), 8.80 (d, J=1.5 Hz, 1 H), 8.62 (s, 1 H), 8.30 (dd, J=4.1, 8.3 Hz, 1 H), 8.05-8.00 (m, 1 H), 5.70 (dd, J=6.7, 6.7 Hz, 1 H), 1.76 (d, J=6.8 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=416 at 3.35 min. Chiral analysis (Method 17) at 2.6 min. Example 68 N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methylpyrimidin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.93 (d, J=2.4 Hz, 1 H), 9.77 (d, J=2.3 Hz, 1 H), 9.59 (d, J=6.4 Hz, 1 H), 8.89 (s, 2 H), 8.67 (s, 1 H), 5.86-5.81 (m, 1 H), 2.39 (s, 3 H), 2.34 (s, 3 H), 1.75 (d, J=7.2 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=349 at 2.65 min. Chiral analysis (Method 25) at 1.89 min. Example 69 6-(4-fluorophenyl)-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO) δ 9.39 (d, J=2.4 Hz, 1 H), 9.25 (d, J=2.5 Hz, 1 H), 9.14 (d, J=6.8 Hz, 1 H), 8.54 (s, 1 H), 8.22 (d, J=8.8 Hz, 1 H), 8.11 (d, J=8.9 Hz, 1 H), 8.00 (ddd, J=3.2, 5.3, 12.1 Hz, 2 H), 7.46 (dd, J=8.9, 8.9 Hz, 2 H), 5.90-5.85 (m, 1 H), 1.80 (d, J=7.2 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=415 at 3.54 min. Chiral analysis (Method 5) at 1.64 min. Example 70 6-(5-fluoropyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.75 (d, J=2.4 Hz, 2 H), 9.44 (d, J=2.4 Hz, 1 H), 8.81 (d, J=2.9 Hz, 1 H), 8.66 (s, 1 H), 8.29 (dd, J=4.3, 8.8 Hz, 1 H), 8.06-8.00 (m, 1 H), 5.23 (d, J=5.4 Hz, 2 H). LCMS (Method 4): [MH ⁺ ]=392 at 3.59 min. Example 71 N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.58 (t, J=5.3 Hz, 1 H), 9.52 (d, J=2.4 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 8.65 (s, 1 H), 7.76 (d, J=1.3 Hz, 1 H), 4.91 (d, J=5.4 Hz, 2 H), 2.59 (s, 3 H), 2.58 (d, J=1.2 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=340 at 2.55 min. Example 72 N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.67 (s, 1 H), 9.53 (d, J=2.4 Hz, 1 H), 9.23 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H), 7.76 (d, J=1.3 Hz, 1 H), 5.01 (d, J=4.1 Hz, 2 H), 2.58 (d, J=1.1 Hz, 3 H), 2.49 (s, 3 H). LCMS (Method 4): [MH ⁺ ]=340 at 2.39 min. Example 73 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.41 (d, J=2.5 Hz, 1 H), 9.37 (t, J=5.7 Hz, 1 H), 9.08 (d, J=2.5 Hz, 1 H), 8.67 (s, 1 H), 7.98-7.94 (m, 2 H), 7.47-7.42 (m, 2 H), 5.03 (d, J=5.5 Hz, 2 H), 2.49 (s, 3 H). LCMS (Method 4): [MH ⁺ ]=337 at 2.65 min. Example 75 6-(5-methylthiazol-2-yl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.54-9.51 (m, 2 H), 9.30 (d, J=2.3 Hz, 1 H), 8.68 (s, 1 H), 7.79 (d, J=1.3 Hz, 1 H), 7.39 (s, 1 H), 4.89 (d, J=5.6 Hz, 2 H), 2.70-2.69 (m, 3 H), 2.61 (d, J=1.1 Hz, 3 H). LCMS (Method 3): [MH ⁺ ]=337 at 3.64 min. Example 76 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.43 (d, J=2.4 Hz, 1 H), 9.29 (d, J=6.7 Hz, 1 H), 9.12 (d, J=2.5 Hz, 1 H), 8.64 (s, 1 H), 8.00-7.94 (m, 2 H), 7.49-7.42 (m, 2 H), 5.94 (dq, J=7.0, 7.0 Hz, 1 H), 1.83 (d, J=7.2 Hz, 3 H). LCMS (Method 3): [MH ⁺ ]=405 at 4.77 min. Example 77 6-(4-fluorophenyl)-N-[(3-methylisoxazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.45 (s, 1 H), 9.34-9.30 (m, 1 H), 9.11 (s, 1 H), 8.71 (s, 1 H), 8.04-7.96 (m, 2 H), 7.48 (t, J=8.5 Hz, 2 H), 6.37 (s, 1 H), 4.97 (d, J=5.0 Hz, 2 H), 2.24 (s, 3 H). LCMS (Method 3): [MH ⁺ ]=336 at 4.02 min. Example 78 N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.84-9.79 (m, 1 H), 9.53 (d, J=2.3 Hz, 1 H), 9.19 (d, J=2.5 Hz, 1 H), 8.73 (s, 1 H), 7.77-7.75 (m, 1 H), 5.13 (d, J=4.3 Hz, 2 H), 2.67 (s, 3 H), 2.57 (d, J=1.1 Hz, 3 H). LCMS (Method 3): [MH ⁺ ]=356 at 3.29 min. Example 79 6-(4-fluorophenyl)-N-[(2-methylthiazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.41-9.40 (m, 1 H), 9.26-9.24 (m, 1 H), 9.16 (s, 1 H), 8.68-8.66 (m, 1 H), 8.02-7.98 (m, 2 H), 7.49-7.45 (m, 2 H), 7.39 (s, 1 H), 4.91-4.90 (m, 2 H), 2.68 (s, 3 H). LCMS (Method 3): [MH+]=352 at 3.65 min. Example 80 6-(4-fluorophenyl)-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.43 (d, J=2.4 Hz, 1 H), 9.35-9.33 (m, 1 H), 9.13 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H), 8.02-7.98 (m, 2 H), 7.50-7.46 (m, 2 H), 4.97-4.95 (m, 2 H), 2.72 (s, 3 H). LCMS (Method 3): [MH+]=337 at 3.33 min. Example 82 N-[(3-methylisoxazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.51-9.50 (m, 2 H), 9.21 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H), 7.76 (s, 1 H), 6.32 (s, 1 H), 4.91-4.90 (m, 2 H), 2.57 (s, 3 H), 2.20 (s, 3 H). LCMS (Method 3): [MH+]=339 at 3.67 min.

Example 83

Single enantiomer 1 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine (Example 83)

Example 84

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

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 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The resulting residue was diluted with saturated NaHCO ₃ solution and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried and the solvent was removed in vacuo. The residue (145 mg) was dissolved in chloroform (1.0 mL) and 1-(5-methyl-1,3,4-thiadiazol-2-yl)ethan-1-amine (93 mg, 0.65 mmol) was added. The reaction mixture was heated in a sealed tube under nitrogen for 18 h at 70 °C. After this time, the resulting mixture was cooled to room temperature. The reaction mixture was diluted with cold water and stirred for 10 min. 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 5% methanol in ethyl acetate (2 x 50 mL). The combined organic phases were passed through phase separating paper and the solvent was removed in vacuo. The residue was purified by chiral preparative HPLC followed by chiral preparative SLC to give the title compound as an off-white solid.

Example 83, single enantiomer 1: 24.7 mg, 13%

¹ H NMR (400 MHz, DMSO): δ 9.71 (d, J=2.4 Hz, 1 H), 9.47 (d, J=2.4 Hz, 1 H), 9.35 (d, J=7.4 Hz, 1 H), 8.80 (d, J=3.0 Hz, 1 H), 8.70 (s, 1 H), 8.28 (dd, J=4.3, 8.8 Hz, 1 H), 8.05-7.99 (m, 1 H), 6.02-5.97 (m, 1 H), 2.67 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=368 at 2.60 min. Chiral analysis (Method 30) at 1.69 min.

Example 84, single enantiomer 2: 27.3 mg, 14%

¹ H NMR (400 MHz, DMSO): δ 9.71 (d, J=2.4 Hz, 1 H), 9.47 (d, J=2.5 Hz, 1 H), 9.35 (d, J=7.5 Hz, 1 H), 8.80 (d, J=2.9 Hz, 1 H), 8.70 (s, 1 H), 8.28 (dd, J=4.3, 8.8 Hz, 1 H), 8.05-7.99 (m, 1 H), 6.02-5.97 (m, 1 H), 2.67 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=368 at 2.60 min. Chiral analysis (Method 30) at 3.1 min.

The following compounds presented in the table below were obtained as single isomers by chiral preparative SLC purification according to the procedure described for the preparation of single enantiomers of 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 87 The only enantiomer of 1 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.73 (d, J=2.4 Hz, 1 H), 9.47 (d, J=2.4 Hz, 1 H), 9.34 (d, J=7.4 Hz, 1 H), 8.69 (s, 1 H), 8.63 (d, J=1.9 Hz, 1 H), 8.11 (d, J=8.2 Hz, 1 H), 7.86 (dd, J=2.1, 8.2 Hz, 1 H), 6.02-5.96 (m, 1 H), 2.67 (s, 3 H), 2.41 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 3): [MH ⁺ ]=364 at 3.59 min. Chiral analysis (Method 23) at 1.0 min. Example 88 The only enantiomer of 2 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.73 (d, J=2.3 Hz, 1 H), 9.47 (d, J=2.4 Hz, 1 H), 9.34 (d, J=7.4 Hz, 1 H), 8.69 (s, 1 H), 8.63 (d, J=1.9 Hz, 1 H), 8.11 (d, J=8.2 Hz, 1 H), 7.86 (dd, J=1.9, 8.2 Hz, 1 H), 6.02-5.96 (m, 1 H), 2.67 (s, 3 H), 2.41 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 3): [MH ⁺ ]=364 at 3.59 min. Chiral analysis (Method 23) at 1.64 min.

Example 91

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

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 phosphorus(V) oxychloride (0.042 ml, 0.45 mmol) was added. The reaction mixture was heated at 95 °C for 2 h and then cooled to room temperature. The solvent was removed in vacuo and (5-methyl-1,3,4-thiadiazol-2-yl)methanamine hydrochloride (93 mg, 0.56 mmol), DIPEA (0.32 ml, 1.87 mmol) and dioxane (3.5 ml) were added to the resulting residue. The reaction mixture was heated at 95°C for an additional 5 h. The reaction mixture was diluted with water and the solid was collected. The precipitate was suspended in DMSO and filtered. The solid was washed with water then ethyl acetate and dried under vacuum to give the title compound (31 mg, 24%) as an off-white solid.

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

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

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 92 6-(4-fluorophenyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.52 (t, J=5.5 Hz, 1 H), 9.42 (d, J=2.4 Hz, 1 H), 9.10 (d, J=2.5 Hz, 1 H), 8.63 (s, 1 H), 8.00-7.94 (m, 2 H), 7.49-7.42 (m, 2 H), 5.07 (d, J=5.6 Hz, 2 H), 2.33 (s, 3 H). LCMS (Method 3): [MH ⁺ ]=337 at 3.36 min. Example 93 6-(4-fluorophenyl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.67-9.62 (m, 1 H), 9.44 (d, J=2.4 Hz, 1 H), 9.11 (d, J=2.5 Hz, 1 H), 8.63 (s, 1 H), 8.01-7.95 (m, 2 H), 7.49-7.42 (m, 2 H), 5.23 (d, J=5.0 Hz, 2 H). LCMS (Method 4): [MH ⁺ ]=391 at 3.84 min. Example 94 6-(5-chloro-2-pyridyl)-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.74 (d, J=2.5 Hz, 1 H), 9.60 (d, J=2.3 Hz, 1 H), 9.23 (d, J=7.1 Hz, 1 H), 8.96 (d, J=1.8 Hz, 1 H), 8.88 (d, J=1.8 Hz, 1 H), 8.64 (s, 1 H), 8.27-8.18 (m, 2 H), 7.93 (d, J=8.1 Hz, 1 H), 5.79-5.70 (m, 1 H), 1.76 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH+]=432 at 3.73 min. Chiral analysis (Method 26) at 1.45 min. Example 95 6-phenyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.44 (d, J=2.4 Hz, 1 H), 9.20 (s, 2 H), 9.18 (d, J=2.4 Hz, 1 H), 9.01-8.98 (m, 1 H), 8.61 (s, 1 H), 7.97-7.95 (m, 2 H), 7.64-7.61 (m, 2 H), 7.51-7.48 (m, 1 H), 5.73-5.71 (m, 1 H), 1.74 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH+]=397 at 3.57 min. Chiral analysis (Method 17) at 2.05 min.

Intermediate connection 11

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

6-Chloropyrido[3,4-d]pyrimidin-4(3H)-one (50 mg, 0.27 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (158 mg, 0.30 mmol) and (6-methylpyridazin-3-yl)methanamine 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 h. 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 MgSO ₄ , filtered and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-20% methanol in dichloromethane to give the title compound (50 mg, 65%).

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

The following compound was prepared according to the procedure described for the preparation of 6-chloro-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine (Intermediate 11):

Intermediate connection No. Chemical name, structure Analytical data, LC-MS Intermediate connection 12 6-Chloro-N-((1R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,4-d]pyrimidin-4-amine
LCMS (Method 4): [MH+]=355.0 at 2.76 min.

Example 26

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

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(0) (30 mg, 0.026 mmol) were placed in a microwave tube. Dioxane (2 mL) and water (0.5 mL) were added and the solution was degassed with nitrogen for 10 min. The reaction mixture was heated to 110 °C for 20 min in the microwave reactor. After returning to room temperature, water (2 mL) was added and the mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic phase was dried over _MgSO4 , filtered and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-20% methanol in dichloromethane to give the title compound (9 mg, 15%).

¹ H NMR (400 MHz, DMSO): δ 9.57 (t, J=5.1 Hz, 1 H), 9.32 (s, 1 H), 8.97 (s, 1 H), 8.71 (s, 1 H), 8.39 (dd, J=5.6, 8.6 Hz, 2 H), 7.76 (d, J=8.6 Hz, 1 H), 7.66 (d, J=8.6 Hz, 1 H), 7.55 (dd, J=8.8, 8.8 Hz, 2 H), 5.21 (d, J=5.6 Hz, 2 H), 2.74 (s, 3 H). LCMS (Method 4): [MH+]=347.0 at 3.18 min.

The following compound was prepared according to the procedure described for the preparation of 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 27 6-(4-Fluorophenyl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.19 (s, 2 H), 9.18 (s, 1 H), 9.04-9.01 (m, 1 H), 8.84 (s, 1 H), 8.56 (s, 1 H), 8.27 (ddd, J=3.2, 5.3, 12.1 Hz, 2 H), 7.43 (dd, J=8.8, 8.8 Hz, 2 H), 5.71-5.64 (m, 1 H), 1.77 (d, J=7.2 Hz, 3 H). LCMS (Method 4): [MH+]=415 at 4.66 min.

Example 28

N-[(6-Methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,4-d]pyrimidin-4-amine

Nitrogen was bubbled through 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-(tributylstannyl)thiazole (271 mg, 0.7 mmol) and potassium carbonate (96 mg, 0.70 mmol) in N,N-dimethylformamide (2 ml) for 5 min, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex 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 for one hour. The reaction mixture was cooled, diluted with ethyl acetate (30 mL) and washed with water (10 mL). The organic phase was filtered through celite® and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (9 mg, 7%) as a brown solid.

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

The following compounds were prepared by the procedure described for the preparation of N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,4-d]pyrimidin-4-amine:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 29 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methyl-2-pyridyl)pyrido[3,4-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.71 (t, J=5.1 Hz, 1 H), 9.23-9.17 (m, 2 H), 8.59 (d, J=10.7 Hz, 2 H), 8.42-8.36 (m, 1 H), 7.86-7.79 (m, 1 H), 7.62-7.57 (m, 1 H), 7.53-7.48 (m, 1 H), 5.04 (d, J=5.4 Hz, 2 H), 2.62-2.59 (m, 3 H), 2.42 (s, 3 H). LCMS (Method 4): [MH+]=344 at 2.33 min. Example 30 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.34 (d, J=7.0 Hz, 1 H), 9.19 (s, 2 H), 9.11 (s, 1 H), 9.05 (s, 1 H), 8.59 (s, 1 H), 7.76 (d, J=1.1 Hz, 1 H), 5.72-5.64 (m, 1 H), 2.56 (s, 3 H), 1.75 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH+]=418 at 4.66 min.

Intermediate connection 13

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

6-Bromopyrido[3,2-d]pyrimidin-4(3H)-one (150 mg, 0.66 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (380 mg, 0.73 mmol) and (6-methylpyridazin-3-yl)methanamine 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 for 6 h. 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 MgSO ₄ , filtered and the solvent was removed in vacuo. 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 an off-white solid.

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

The following compound was prepared according to the procedure described for the preparation of 6-Bromo-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 13):

Intermediate connection No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Intermediate connection 14 (R)-6-Bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine
LCMS (Method 4): [MH+]=399.0 at 3.03 min.

Example 31

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

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]dichloropalladium(II) (11 mg, 0.016 mmol) were placed in a microwave tube. 1,4-Dioxane (2 mL) and water (0.5 mL) were added and the solution was degassed with nitrogen for 10 min. The reaction mixture was heated to 110 °C for 20 min in the microwave reactor. After returning to room temperature, water (2 ml) was added and the mixture was extracted with ethyl acetate (2 x 15 ml). The combined organic phases were dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-20% methanol in dichloromethane to give the title compound (22 mg, 42%) as an off-white solid.

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

Example 32

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

Nitrogen was bubbled through 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-(tributylstannyl)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 for 18 h. The crude product was cooled to room temperature, diluted in methanol, and loaded onto an SCX cartridge. The cartridge was rinsed with methanol, and the filtrate was collected, eluting with 7 M ammonia in methanol. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (19 mg, 26% yield).

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

The following compounds were synthesized by the procedure used for the preparation of N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]-pyrimidin-4-amine:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 33 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.84 (d, J = 8.9 Hz, 1 H), 8.65 (s, 1 H), 8.56 (d, J = 1.8 Hz, 1 H), 8.43 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 7.71-7.63 (m, 2 H), 5.93-5.85 (m, 1 H), 2.44 (d, J = 11.0 Hz, 6 H), 1.87 (d, J = 7.0 Hz, 3 H). LCMS (Method 4): [MH+] = 348.3 at 2.97 min. Example 34 N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.07 (dd, J=6.0, 6.0 Hz, 1 H), 8.51-8.48 (m, 2 H), 8.24 (d, J=8.8 Hz, 1 H), 7.79 (s, 1 H), 7.59 (d, J=8.7 Hz, 1 H), 7.52 (d, J=8.7 Hz, 1 H), 5.08 (d, J=6.0 Hz, 2 H), 2.61 (s, 3 H), 2.58 (d, J=1.1 Hz, 3 H). LCMS (Method 4): [MH+]=350 at 2.68 min.

Example 35

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

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) were added potassium carbonate (145 mg, 1.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (86 mg, 0.10 mmol) and copper iodide (20 mg). The mixture was stirred for 10 min and then 3-methyl-5-tributylstannylthiazole (402 mg, 1.05 mmol) was added. The reaction mixture was heated to 100 °C for 16 h. After returning to room temperature, water (10 ml) was added and the reaction mixture was extracted with dichloromethane (3 x 10 ml). The combined organic phases were filtered through a hydrophobic frit. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (7.1 mg, 33%) as an off-white solid.

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

Example 36

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

Nitrogen was bubbled through 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-tributylstannylthiazole (195 mg, 0.50 mmol) and copper iodide (9.5 mg, 0.05 mmol) in N,N-dimethylformamide (4.0 ml) for 5 min, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (41 mg, 0.05 mmol) was added. The reaction mixture was heated to 100 °C for one hour. After returning to room temperature, water (10 ml) was added and the reaction mixture was extracted with dichloromethane (3 x 10 ml). The combined organic phases were filtered through a hydrophobic frit. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (6.8 mg, 7%) as an off-white solid.

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

Intermediate connection 15

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

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

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

Example 37

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

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) were added in turn (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (356 mg, 0.68 mmol) and diisopropylethylamine (2.7 ml, 15.6 mmol). The resulting mixture was heated to 50 °C for one hour, then (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-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 x 20 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (13 mg, 5%) as an off-white solid.

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

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

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 38 6-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.12 (d, J=8.3 Hz, 1 H), 8.59-8.51 (m, 4 H), 8.23 (d, J=8.9 Hz, 1 H), 7.41 (dd, J=8.9, 8.9 Hz, 2 H), 5.92-5.84 (m, 1 H), 2.35 (s, 3 H), 1.81 (d, J=7.2 Hz, 3 H). LCMS (Method 3): [M+H]=351.3 at 3.92 min.

Intermediate connection 16

6-Brompteridin-4(3H)-one

Acetic anhydride (10 mL, 105.79 mmol) was added to a suspension of 3-amino-6-bromopyrazine-2-carboxamide (2 g, 9.22 mmol) in triethyl orthoformate (20 mL, 120.24 mmol). The reaction mixture was heated to 120 °C for one hour and at 90 °C for 2 days. After returning to room temperature, the reaction mixture was concentrated in vacuo. The residue was triturated with IPA, filtered and dried to give the title compound (1.3 g, 62%) as a brown solid.

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

Intermediate connection 17

6-(4-Fluorophenyl)pteridin-4(3H)-one

6-Bromopteridin-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]dichloropalladium(II) (97 mg, 0.132 mmol) were placed in a microwave tube. Dioxane (5 mL) and water (0.5 mL) were added and the solution was degassed with nitrogen for 10 min. The reaction mixture was heated to 110 °C for 35 min in the microwave reactor. After returning to room temperature, water (5 mL) was added and the mixture was extracted with CHCl ₃ /IPA (60:40) (3×20 mL). The combined organic phases were dried over MgSO4 _, filtered and the solvent removed in vacuo to give the title compound (280 mg, 88%) as a red solid.

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

Example 39

6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridin-4-amine

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

To a solution of 6-(4-fluorophenyl)pteridin-4(3H)-one (Intermediate 17) (280 mg, 1.16 mmol) in thionyl chloride (2.6 ml, 35.98 mmol) was added N,N-dimethylformamide (0.1 ml, 0.01 mmol) and the mixture was heated at reflux for three hours. After returning to room temperature, toluene (5 ml) was added and the solvent was removed in vacuo. Toluene was added two more times and evaporated in vacuo to give the title compound, which was taken to the next step without further purification.

Step 2: Preparation of 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridin-4-amine

4-Chloro-6-(4-fluorophenyl)pteridine (120 mg, 0.460 mmol), 6-methylpyridazin-3-yl)methanamine 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 h. The mixture was then cooled to room temperature and loaded into an SCX cartridge. The cartridge was rinsed with methanol, and the filtrate was collected, eluting with 7 M ammonia in methanol. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to afford the title compound (8.6 mg, 7% yield).

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

Example 40

6-(4-Fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pteridin-4-amine

To a solution of 6-(4-fluorophenyl)pteridin-4(3H)-one (Intermediate 17) (40 mg, 0.165 mmol) in N,N-dimethylformamide (4 ml) were added in turn (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (95 mg, 0.18 mmol), diisopropylethylamine (0.71 ml, 4.1 mmol) and 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (36 mg, 0.18 mmol). The resulting mixture was heated to 50 °C for 2 h. 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 frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (113 mg, 12%) as a yellow solid.

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

The following compounds, presented in the table below, were prepared according to the procedure described for the preparation of 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pteridin-4-amine:

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 41 (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pteridin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.77 (s, 1 H), 9.23 (s, 2 H), 9.20 (d, J=8.2 Hz, 1 H), 8.64-8.57 (m, 3 H), 7.47 (dd, J=8.8, 8.8 Hz, 2 H), 5.82-5.76 (m, 1 H), 1.81 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [M+H]=416.2 at 4.56 min. Example 42 6-(4-Fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pteridin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.76 (s, 1 H), 9.53 (dd, J=6.2, 6.2 Hz, 1 H), 8.63 (s, 1 H), 8.61-8.56 (m, 2 H), 8.53 (d, J=2.0 Hz, 1 H), 7.72 (dd, J=2.4, 7.9 Hz, 1 H), 7.45 (dd, J=8.9, 8.9 Hz, 2 H), 7.22 (d, J=8.0 Hz, 1 H), 4.83 (d, J=6.4 Hz, 2 H), 2.44 (s, 3 H). LCMS (Method 3): [M+H]=347.3 at 2.58 min.

The following compounds, presented in the table below, were obtained as individual isomers by chiral preparative SFC purification of the appropriate racemic mixture described above.

Example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Example 43 The only enantiomer of 1 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.78 (d, J=2.3 Hz, 1 H), 9.52 (d, J=2.0 Hz, 1 H), 9.37 (d, J=7.1 Hz, 1 H), 8.68 (s, 2 H), 8.16 (d, J=8.1 Hz, 1 H), 7.90 (dd, J=1.4, 8.0 Hz, 1 H), 5.90-5.83 (m, 1 H), 2.45 (s, 3 H), 2.38 (s, 3 H), 1.80 (d, J=7.1 Hz, 3 H). LCMS (Method 4) [MH+]=348 at 2.87 min. Chiral analysis (Method 10) at 1.60 min. Example 44 The only enantiomer of 2 N-(1-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.78 (d, J=2.3 Hz, 1 H), 9.52 (d, J=2.0 Hz, 1 H), 9.37 (d, J=7.1 Hz, 1 H), 8.68 (s, 2 H), 8.16 (d, J=8.1 Hz, 1 H), 7.90 (dd, J=1.4, 8.0 Hz, 1 H), 5.90-5.83 (m, 1 H), 2.45 (s, 3 H), 2.38 (s, 3 H), 1.80 (d, J=7.1 Hz, 3 H). LCMS (Method 3) [MH+]=348 at 3.49 min. Chiral analysis (Method 10) at 2.34 min. Example 45 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.45 (d, J=2.3 Hz, 1 H), 9.23-9.18 (m, 2 H), 8.68 (s, 1 H), 8.04-7.99 (m, 2 H), 7.49 (dd, J=8.8, 8.8 Hz, 2 H), 5.87 (d, J=6.8 Hz, 1 H), 2.38 (s, 3 H), 1.80 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH+]=351 at 3.21 min. Chiral analysis (Method 10) at 1.09 min. Example 46 The only enantiomer of 2 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.45 (d, J=2.5 Hz, 1 H), 9.22-9.18 (m, 2 H), 8.68 (s, 1 H), 8.04-7.99 (m, 2 H), 7.49 (dd, J=8.8, 8.8 Hz, 2 H), 5.89-5.83 (m, 1 H), 2.38 (s, 3 H), 1.79 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH+]=351 at 3.18 min. Chiral analysis (Method 10) at 1.45 min. Example 47 The only enantiomer of 1 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine ¹ H NMR (400 MHz, DMSO): δ 9.57 (d, J=2.0 Hz, 1 H), 9.47 (d, J=4.3 Hz, 1 H), 9.37 (d, J=2.0 Hz, 1 H), 8.69 (s, 1 H), 7.82 (s, 1 H), 5.90-5.84 (m, 1 H), 2.62 (s, 3 H), 2.38 (s, 3 H), 1.79 (d, J=7.1 Hz, 3 H). LCMS (Method 3) [MH+] = 354 at 3.31 min. Chiral analysis (Method 5) at 1.21 min. Example 48 The only enantiomer of 2 N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.57 (d, J=2.0 Hz, 1 H), 9.47 (d, J=4.3 Hz, 1 H), 9.37 (d, J=2.0 Hz, 1 H), 8.69 (s, 1 H), 7.82 (s, 1 H), 5.90-5.84 (m, 1 H), 2.62 (s, 3 H), 2.38 (s, 3 H), 1.79 (d, J=7.1 Hz, 3 H). LCMS (Method 3) [MH+] = 354 at 3.31 min. Chiral analysis (Method 5) at 1.52 min. Example 102 The only enantiomer of 1 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.43 (d, J=2.5 Hz, 1 H), 9.28 (d, J=6.7 Hz, 1 H), 9.11 (d, J=2.4 Hz, 1 H), 8.64 (s, 1 H), 8.00-7.95 (m, 2 H), 7.49-7.42 (m, 2 H), 5.94 (dq, J=7.0, 7.0 Hz, 1 H), 1.83 (d, J=7.1 Hz, 3 H). LCMS (Method 4): [MH ⁺ ]=405 at 4.12 min. Chiral analysis (Method 24) at 1.02 min. Example 103 The only enantiomer of 1 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (Isomer 1)
¹ H NMR (400 MHz, DMSO): δ 9.40 (d, J=2.5 Hz, 1 H), 9.20-9.13 (m, 2 H), 8.69 (s, 1 H), 7.99-7.94 (m, 2 H), 7.45 (dd, J=8.9, 8.9 Hz, 2 H), 6.01-5.96 (m, 1 H), 2.67 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH+]=367 at 2.96 min. Chiral analysis (Method 10) at 2.73 min. Example 104 The only enantiomer of 2 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine (Isomer 2)
¹ H NMR (400 MHz, DMSO): δ 9.40 (d, J=2.5 Hz, 1 H), 9.20-9.13 (m, 2 H), 8.69 (s, 1 H), 7.99-7.94 (m, 2 H), 7.45 (dd, J=8.9, 8.9 Hz, 2 H), 6.01-5.96 (m, 1 H), 2.67 (s, 3 H), 1.82 (d, J=7.0 Hz, 3 H). LCMS (Method 4): [MH+]=367 at 2.95 min. Chiral analysis (Method 10) at 3.86 min. Example 105 The only enantiomer of 1 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.36 (d, J=2.4 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 9.00-8.98 (m, 1 H), 8.57 (s, 1 H), 8.47 (d, J=2.4 Hz, 1 H), 8.00-7.92 (m, 3 H), 7.47-7.41 (m, 2 H), 5.90-5.84 (m, 1 H), 1.65 (d, J=6.8 Hz, 3 H). LCMS (Method 4): [MH+]=382 at 4.3 min. Chiral analysis (Method 31) at 1.41 min. Example 106 The only enantiomer of 2 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine
¹ H NMR (400 MHz, DMSO): δ 9.35 (d, J=2.4 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 9.00-8.98 (m, 1 H), 8.55 (s, 1 H), 8.47 (d, J=2.4 Hz, 1 H), 8.00-7.94 (m, 3 H), 7.46-7.42 (m, 2 H), 5.90-5.84 (m, 1 H), 1.65 (d, J=6.8 Hz, 3 H). LCMS (Method 4): [MH+]=382 at 4.3 min. Chiral analysis (Method 31) at 2.11 min.

PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS ACCORDING TO THE INVENTION

In vitro electrophysiology analysis for P2X ₃ .

_P2X3 receptor expressing cells were grown according to standard practice and maintained at 37°C in a _CO2 atmosphere with 5% humidification. Cells were seeded into T175 flasks 2 days prior to the assay day and dissociated from flasks using TrypLE when grown to 80-90% confluence. Dissociated cells were resuspended in serum-free medium at a cell density of 3 x ¹⁰⁶ cells/mL and loaded onto a 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. The intracellular assay solution contains 140 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES at pH 7.2. Agonist stock solutions were prepared in _H2O and diluted in wash fluid before use. All antagonists were prepared as 10 mM stock solutions in DMSO and diluted in wash fluid before use. All experiments were performed in a whole-cell patch-clamp configuration at room temperature with voltages on 384 individual cells simultaneously recorded at -60 mV on a Sophion Qube. Two initial responses were obtained using α,β-MeATP (800 nM) followed by agonist applications washed with extracellular assay buffer containing 0.5 U/mL apyrase. Following application of the second agonist, the antagonist is incubated in the absence of α,β-MeATP for 10 min. After pre-incubation of the antagonist, 800 nM α,β-MeATP and the antagonist are co-administered to determine the inhibitory effect of the antagonist. One concentration of antagonist is measured relative to a single cell, with different concentrations of antagonist applied to other cells on the recording substrate 384. The amplitude of the control P2X ₃ current is taken from the amplitude of the peak current from the second agonist response before pre-incubation with the antagonist. The peak amplitude of the P2X ₃ current in the presence of the antagonist is used to calculate the inhibitory effect at each concentration of antagonist according to the following equation:

The fraction of _P2X3 inhibition = (amplitude of the control _P2X3 peak - amplitude of the antagonist _P2X3 peak)/amplitude of the control _P2X3 peak) * 100.

Concentration-response curves are constructed for ten different concentrations, where each antagonist concentration is tested on at least two separate cells. The concentration of antagonist to inhibit the P2X ₃ current by 50% (IC ₅₀ ) is determined by fitting the data with the following equation:

Y=a+[(b-a)/(1+10^((log c-x)d)]

Where 'a' is the minimum response, 'b' is the maximum response, 'c' is the IC ₅₀ and 'd' is the Hill slope.

The results for individual compounds are presented below in Table 8 and are expressed as a range of activity.

Table 8 Example No. h P2X ₃ 1 +++ 2 +++ 3 ++ 4 ++ 5 + 6 +++ 7 +++ 8 ++ 9 +++ 10 +++ 11 +++ 12 ++ 13 +++ 14 +++ 15 +++ 16 +++ 17 ++ 18 + 19 +++ 20 +++ 21 + 22 + 23 + 24 + 25 + 26 +++ 27 +++ 28 +++ 29 ++ 30 +++ 31 ++ 32 +++ 33 ++ 34 ++ 35 +++ 36 +++ 37 ++ 38 + 39 ++ 40 ++ 41 ++ 42 +++ 43 + 44 +++ 45 + 46 +++ 47 ++ 48 ++ 49 +++ 50 +++ 51 ++ 52 +++ 54 ++ 55 ++ 56 ++ 58 +++ 59 + 60 ++ 63 ++ 65 + 66 ++ 67 ++ 68 ++ 69 +++ 70 ++ 71 ++ 72 ++ 73 ++ 75 ++ 76 +++ 77 ++ 78 ++ 79 ++ 80 ++ 82 ++ 83 ++ 84 ++ 87 + 88 +++ 91 ++ 92 93 ++ 94 + 95 +++ 102 ++ 103 + 104 ++ 105 ++ 106 + 107 +++

where the compounds are classified according to their potency in terms of their inhibitory effect on the P2X ₃ isoform according to the following classification criteria:

+++: pIC ₅₀ hP2X ₃ > 6.5

++: 6.5 <pIC ₅₀ hP2X ₃ > 5.5

+: pIC ₅₀ hP2X ₃ <5.5

In vitro electrophysiology analysis for P2X _2/3

The same assay protocol is used for the P2X _2/3 assay as for the P2X ₃ assay with two modifications: 1) 10 μM ATP is used as the agonist; and 2) the mean current amplitude is measured seven seconds after agonist application.

The results from Table 9 show that the exemplary compounds of the present invention are selective P2X ₃ agonists.

Table 9 Example No. hP2X ₃ hP2X _2/3 3 ++ + 7 +++ + 9 +++ ++ 11 +++ + 13 +++ + 14 +++ ++ 15 +++ ++ 19 +++ + 27 +++ + 32 +++ + 34 ++ + 42 +++ + 46 +++ + 49 +++ + 51 ++ + 52 +++ + 55 ++ + 67 ++ + 68 ++ + 69 +++ + 78 ++ + 88 +++ + 102 ++ + 104 ++ + 107 +++ +

where the compounds are classified according to their potency in terms of their inhibitory effect on P2X ₃ and P2X _2/3 isoforms according to the following classification criteria:

+++: pIC ₅₀ hP2X ₃ or hP2X _2/3 > 6.5

++: 6.5 <pIC ₅₀ hP2X ₃ or hP2X _2/3 > 5.5

+: pIC ₅₀ hP2X ₃ or hP2X _2/3 <5.5

Comparative example A

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

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

6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (202 mg, 0.89 mmol) (intermediate 1), 5-hydroxymethyl-2-methylpyridine (110 mg, 0.89 mmol) and triphenylphosphine (328 mg, 1.25 mmol) were stirred in dry THF (7 ml) and a solution of diisopropyl azodicarboxylate (229 µl, 1.16 mmol) in dry THF (3 ml) was added dropwise and stirred at room temperature for 6 h. 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 in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in DCM to give 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine (164 mg, 55%).

¹ H NMR (400 MHz, DMSO): δ 9.08 (d, J=2.6 Hz, 1 H), 8.89 (s, 1 H), 8.67 (d, J=2.6 Hz, 1 H), 8.55 (d, J=2.1 Hz, 1 H), 7.72 (dd, J=2.4, 8.0 Hz, 1 H), 7.24 (d, J=8.0 Hz, 1 H), 5.20 (s, 2 H), 2.44 (s, 3 H).

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

Nitrogen was bubbled through a mixture of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine (84 mg, 0.254 mmol), 4-fluorophenylboronic acid, pinacol ester (76 mg, 0.342 mmol), and cesium fluoride (116 mg, 0.761 mmol) in DMF (1 mL) and water (0.3 mL). After 5 min, tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added and the resulting mixture was heated at 95 °C for 16 h. The reaction mixture was 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 frit, combined, and the solvent removed in vacuo. Purification by preparative reverse-phase HPLC gave 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrmidine (52 mg, 59%) as 0.5 equiv. formate.

¹ H NMR (400 MHz, DMSO): δ 9.35 (d, J=2.8 Hz, 1 H), 8.92 (s, 1 H), 8.73 (d, J=2.5 Hz, 1 H), 8.61 (d, J=1.5 Hz, 1 H), 8.32 (s, 0.5 H), 7.97 (dd, J=5.3, 8.6 Hz, 2 H), 7.77 (dd, J=2.1, 8.0 Hz, 1 H), 7.42 (dd, J=8.8, 8.8 Hz, 2 H), 7.29 (d, J=8.1 Hz, 1 H), 5.27 (s, 2 H), 2.49 (s, 3 H).

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

The following compound, shown in the table below, was prepared by the procedure described for the preparation of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine.

Comparative example No. Chemical name, structure Analytical data, ¹ H NMR, LC-MS Comparative example B
6-(5-methylpyridin-2-yl)-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine ¹ H NMR (400 MHz, DMSO): δ 9.70 (d, J=2.3 Hz, 1 H), 9.14 (d, J=2.3 Hz, 1 H), 8.92 (s, 1 H), 8.66-8.60 (m, 2 H), 8.18 (d, J=8.1 Hz, 1 H), 7.83 (d, J=6.8 Hz, 1 H), 7.78 (dd, J=1.9, 8.0 Hz, 1 H), 7.29 (d, J=8.1 Hz, 1 H), 5.27 (s, 2 H), 2.49 (s, 3 H), 2.42 (s, 3 H). LCMS (Method 3): [MH+]=344 at 3.31 m

The activity of comparative examples A and B is tested in an in vitro electrophysiology assay for P2X ₃ as described above.

The results for individual compounds are presented below in Table 10 and are expressed as a range of activity.

Table 10 Comparative example No. h P2X ₃ A not active IN not active

Inactive: pIC ₅₀ hP2X ₃ <4.5.

Claims (97)

1. A compound selected from the group consisting of: (R)-6-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine, (R)-6-(5-methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, (R)-6-(5-chloropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, (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, N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)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-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[3,4-d]pyrimidin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]-pyrimidin-4-amine, N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)pteridin-4-amine, 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 1 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 2 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, 6-(5-methylthiazol-2-yl)-N-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine, 6-(5-methylthiazol-2-yl)-N-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]pyrido[2,3-d]pyrimidin-4-amine, N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine, 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-oxadiazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, 6-(5-methylpyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine, 6-(5-fluoro-2-pyridyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, (R)-6-(5-fluoropyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methylpyrimidin-2-yl)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-(5-fluoropyridin-2-yl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine, N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine, N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine, 6-(5-methylthiazol-2-yl)-N-[(2-methylthiazol-4-yl)methyl]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, 6-(4-fluorophenyl)-N-[(3-methylisoxazol-5-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine, N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-6-(5-methylthiazol-2-yl)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-oxadiazol-3-yl)methyl]pyrido[2,3-d]pyrimidin-4-amine, N-[(3-methylisoxazol-5-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[2,3-d]pyrimidin-4-amine, single enantiomer 1 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 2 6-(5-fluoro-2-pyridyl)-N-[1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]pyrido[2,3-d]pyrimidin-4-amine, single enantiomer 1 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer of 2 N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-6-(5-methylpyridin-2-yl)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-oxadiazol-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-(5-chloro-2-pyridyl)-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, 6-phenyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 1 6-(4-fluorophenyl)-N-[1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 1 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, the only enantiomer of 2 6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, the single enantiomer 1 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine, the only enantiomer of 2 N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine, N-[1-(3,5-difluoro-2-pyridyl)ethyl]-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-amine, 6-(5-methylthiazol-2-yl)-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]pyrido[2,3-d]pyrimidin-4-amine. 2. A compound selected from the group consisting of: (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; N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)pyrido[2,3-d]-pyrimidin-4-amine; 6-(5-chloropyridin-2-yl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine; 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine; 6-(5-chloropyridin-2-yl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)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; 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)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one; 1-(4-(4-(((6-methylpyridazin-3-yl)methyl)amino)-6-(5-methylthiazol-2-yl)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; 1-(4-(6-methyl-4-(((6-methylpyridazin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethan-1-one, 2-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-(5-methyl-1,2,4-oxadiazol-3-yl)ethan-1-ol, (R)-6-(4-fluorophenyl)-N-(1-(5-methyl-1,3,4-oxadiazol-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-oxadiazol-3-yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine, 6-(4-fluorophenyl)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-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. 3. A compound selected from the group consisting of: 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine; N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,4-d]pyrimidin-4-amine; N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methyl-2-pyridyl)pyrido[3,4-d]pyrimidin-4-amine; 6-(5-methylthiazol-2-yl)-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; N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine; (R)-6-(5-methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine; (R)-6-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-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-oxadiazol-5-yl)ethyl)pyrido[3,2-d]pyrimidin-4-amine. 4. A compound selected from the group consisting of: 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pteridin-4-amine; 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)pteridin-4-amine; (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)pteridin-4-amine. 5. A pharmaceutical composition having an inhibitory effect on the P2X ₃ receptor, containing a therapeutically effective amount of a compound defined in any one of paragraphs 1-4, or a pharmaceutically acceptable salt thereof in a mixture with one or more pharmaceutically acceptable carriers or excipients. 6. A pharmaceutical composition according to item 5 for oral administration. 7. A compound according to any one of claims 1-4 or a pharmaceutical composition thereof according to claims 5 and 6 for use as a medicinal product having an inhibitory effect on the P2X ₃ receptor. 8. A compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claims 5 and 6 for use in the treatment of any disease in which P2X ₃ receptors are involved. 9. The compound of any one of claims 1 to 4 or the pharmaceutical composition of claims 5 and 6 for use in the prevention and/or treatment of respiratory diseases, including cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm. 10. The compound or pharmaceutical composition according to claim 9 for use in the treatment of chronic cough. 11. Compound (R)-5-(1-((6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide.