Chemical compound

Abstract

Na v 1.8 To inhibit voltage-dependent sodium ion channels and for treating Na-mediated diseases such as pain and pain-related diseases and heart diseases v 1.8 To provide compounds and pharmaceutical compositions and their use for treating intervening diseases

Description

Technical Field

[0001] The present invention relates to Na v 1.8 inhibitory compounds or pharmaceutically acceptable salts or tautomers thereof, corresponding pharmaceutical compositions or formulations, methods or processes for preparing the compounds, methods for treating pain and pain-related diseases as well as heart diseases, compounds for use in treatment, use for treatment and / or combination therapies for treatment.

Background Art

[0002] Pain is a protective mechanism by which animals avoid potential tissue damage, but there are many diseases in which pain loses its usefulness and becomes a burden. Signs that pain loses its usefulness can be broadly classified as those triggered by nerve damage or injury (neuropathic pain), those in which an inflammatory response or abnormal metabolic regulation sensitizes the pain response (inflammatory pain), and those in which an injury or surgical procedure causes a short-term increase in the pain response (postoperative / outpatient pain).

[0003] Voltage-gated sodium ion channels generate electrical signals in all excitable tissues due to the underlying cause of threshold setting and the rising phase of the action potential. There are nine different isoforms of voltage-gated sodium ion channels. Na v 1.1, Na v 1.7, Na v 1.8 and Na v 1.9, which are named, are mainly expressed on peripheral nerves, where they control neuronal excitability. Na v 1.5 is the main sodium channel isoform expressed in cardiomyocytes, and Na v 1.4 is expressed and functions in skeletal muscle, while Na v 1.1, Na v 1.2, Na v 1.3 and Na v1.6 is expressed to some extent widely in the central nervous system (CNS) and in the peripheral nervous system. The major role of these nine voltage-gated sodium ion channels is equivalent to their controlling sodium influx into cells, but the biophysical properties that greatly affect the physiological profile of each of these cell types vary (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are clinically utilized as anti-arrhythmic and anti-seizure therapies, and these include lidocaine, carbamazepine, amitriptyline, and mexiletine. However, since these agents do not show selectivity among different sodium channel isoforms, their therapeutic usefulness is greatly reduced by adverse side effects and is more greatly mediated by activity in the CNS and heart. This has encouraged efforts to develop novel pharmaceuticals that are selective for specific sodium channel isoforms to avoid side effects in the CNS and cardiovascular system.

[0005] Na v The Na1.8 channel is expressed in neurons of the dorsal root ganglion (DRG) and is highly expressed in the small-diameter neurons of this tissue that form pain-sensing C- and Aδ -nerve fibers (Abrahamsen, 2008; Amaya, 2000; Novakovic, 1998). Due to its prominent physiological role and restricted expression profile in this tissue type, the channel was proposed as a therapeutic target for analgesia soon after it was first cloned from rat DRG (Akopian, 1996). v The Na1.8 channel was subsequently identified, cloned, and characterized from human DRG tissue (Rabart 1998). v The closest molecular relative of Na1.8 is Na1.5, which shares approximately 60% sequence homology. v Na1.8 was previously known as SNS (sensory neuron sodium channel), PN3 (peripheral nerve sodium channel type 3), v Na1.8. v1.8 exhibits characteristic pharmacological properties in its resistance to being blocked by tetrodotoxin and is thus also described as a TTX-resistant sodium channel.

[0006] Na as a therapeutic target for pain symptoms v Support for 1.8 comes from several sources. Na v It has been found that in DRG neurons, most of the current conducts during the rising phase of the action potential (Blair & Bean, 2002), and due to its reactivation rate, it is also important for the ability of these neurons to fire respectively (Blair and Bean, 2003). Na v Increased expression and function of 1.8 have been reported in response to painful stimuli such as inflammatory diet (England 1996 & Gold 1996), nerve injury (Roza 2003 & Ruangsri 2011), and painful neuroma (Black 2008 & Coward 2000). Knockout of the gene encoding Nav1.8 in mice resulted in a decrease in the pain phenotype, especially in response to inflammatory challenges (Akopian 1999). Knockdown of the mRNA encoding Nav1.8 also led to a decrease in the pain phenotype in rodent models, especially in neuropathic models (Lai 2002). Pharmacological treatment with selective small molecule inhibitors has demonstrated effectiveness in rodent models of both neuropathic pain and inflammatory pain (Jarvis 2007 & Payne 2015). Na v Genetic evidence indicates that gain-of-function mutations are also present in patients with chronic neuropathic pain, in whom multiple gain-of-function mutations have been reported to cause transient painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). Summary of the Invention

[0007] Thus, novel compounds, in particular NaCl, having improved solubility and therefore more advantageous for alternative routes of administration, such as intravenous administration, for use in the treatment of pain and pain-related disorders, as well as cardiac disorders, are available. v There is a need for the development of Na 1.8 inhibitor compounds. v 1.8 Compounds with inhibitory activity and Na v This need is satisfied by providing prodrugs of compounds having 1.8 inhibitory activity and the use of such compounds and prodrugs in the treatment of pain and pain-related disorders, and cardiac disorders. The prodrugs of the present invention have, in particular, improved solubility compared to their respective parent compounds, and therefore may be useful for the treatment of pain and pain-related disorders where intravenous administration may be beneficial or preferred, such as in the treatment of acute pain.

[0008] In one embodiment, the following: [ka] The present invention provides a compound selected from the group consisting of:

[0009] In another aspect, the following: [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0010] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0011] In another aspect, there is provided a method of treating pain or a pain-related disorder in a human in need of such treatment, comprising administering to said human a compound of the invention or a tautomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the invention.

[0012] In another aspect, there is provided a method for treating atrial fibrillation in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0013] In another aspect, there is provided a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in therapy.

[0014] In another aspect, there is provided a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in the treatment of pain or a pain-related disorder.

[0015] In another aspect, there is provided a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in the treatment of atrial fibrillation.

[0016] In another aspect, there is provided the use of a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of pain or a pain-related disorder.

[0017] In another aspect, there is provided the use of a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of atrial fibrillation. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

[0019] Various publications, papers and patents are cited or described throughout the background art section and the specification. The consideration of the documents, acts, materials, devices, articles or the like included in this specification is for the purpose of providing context for the present disclosure. Such consideration does not admit that any or all of these contents form part of the prior art with respect to the present disclosure.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, the specific terms used herein have the meaning as set forth herein.

[0021] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0022] The definitions of the various groups and substituents of any of the formulas disclosed herein, or of the pharmaceutically acceptable salts thereof provided throughout this specification, are intended to specifically describe each compound species disclosed herein, as well as the groups of one or more compound species.

[0023] The term "alkyl" represents a straight-chain or branched-chain saturated hydrocarbon radical having a specific number of carbon atoms. For example, the term "(C1-C6)alkyl" represents an alkyl group having 1 to 6 carbon atoms, and the term "(C1-C3)alkyl" represents an alkyl group having 1 to 3 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl. In some embodiments, "Me" represents a methyl group.

[0024] The terms "halogen" and "halo" represent chloro (-Cl), fluoro (-F), bromo (-Br), or iodo (-I) substituents.

[0025] When the term "alkyl" is used in combination with other substituents such as "haloalkyl", the term "alkyl" is intended to include a divalent straight-chain or branched-chain hydrocarbon radical whose point of attachment is through the alkyl portion.

[0026] The term "haloalkyl" represents a straight-chain or branched-chain carbon radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety having a specific number of carbon atoms. For example, the term "halo(C1-C6)alkyl" represents a straight-chain or branched-chain carbon radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms. Examples of "haloalkyl" groups include, but are not limited to, -CH2F (fluoromethyl), -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[0027] Compound In one aspect of the present invention, the following:

Chemical formula

[0028] Such compounds of the present invention are prodrugs of the respective parent compounds which are Na v 1.8 inhibitory compounds. The term "prodrug" represents a compound which is a drug precursor that releases the parent compound in vivo by a metabolic process after administration and / or absorption. Usually, prodrugs have less biological activity than the parent compound. Prodrugs can also improve the physical properties and / or efficacy of the parent compound, such as lower toxicity and fewer undesirable effects due to greater control of absorption, blood levels, metabolic distribution and / or intracellular uptake of the parent compound. Prodrugs can also have higher solubility than the corresponding parent compound.

[0029] When a prodrug is administered to a subject such as a human, the prodrug moiety is cleaved, thereby yielding the parent compound. The terms "parent compound" and "parent drug" are used interchangeably herein and refer to a bioactive entity that is released by an enzymatic action of a metabolic process or degradation product reaction, or a chemical process after prodrug administration. The parent compound can also be a starting material for the preparation of the corresponding prodrug. Without wishing to be bound by any theory, the Na v 1.8 inhibitory activity is, by nature, due to the formation of the parent compound from the cleavage of the prodrug.

[0030] The prodrugs of the present invention generally have higher aqueous solubility than the corresponding parent compounds. This higher solubility facilitates the administration of higher doses of the prodrug and results in a higher drug load per unit dose. Accordingly, the prodrug compounds of the present invention can be advantageous for intravenous (IV) formulations and administrations, and thus are useful for the treatment of pain and pain-related disorders such as the treatment of acute pain where higher doses of administration or administration via the IV route may be beneficial.

[0031] In one embodiment, the following:

Chemical formula

[0032] In one embodiment, the following:

Chemical formula

[0033] In one embodiment, the following:

Chemical formula

[0034] In one embodiment, the following: [Chemical formula] There is provided a compound represented by the following formula, or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, the following: [Chemical formula] There is provided a compound represented by the following formula, or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, the following: [Chemical formula] There is provided a compound selected from the group consisting of the following formulae, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. Such compounds of the present invention are the parent compounds of specific prodrugs of the present invention and have Na v 1.8 inhibitory activity.

[0037] In certain embodiments, the following: [Chemical formula] There is provided a compound represented by the following formula, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0038] In certain embodiments, the following: [Chemical formula] There is provided a compound represented by the following formula, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0039] Salt Reference to a compound of the present invention and / or its corresponding tautomer or a salt thereof herein is to be understood to include the compound and / or its corresponding tautomer as the free base or acid, or as its salt, for example, as its pharmaceutically acceptable salt. Thus, in one embodiment, the present invention is directed to a compound of the present invention and / or its corresponding tautomer. In another embodiment, the present invention is directed to a salt of a compound of the present invention and / or its corresponding tautomer. In a further embodiment, the present invention is directed to a pharmaceutically acceptable salt of a compound of the present invention and / or its corresponding tautomer. In another embodiment, the present invention is directed to a compound of the present invention and / or its corresponding tautomer, or a salt thereof. In another embodiment, the present invention is directed to a compound of the present invention and / or its corresponding tautomer, or a pharmaceutically acceptable salt thereof.

[0040] Due to its potential use in medicine, salts of the compounds of the present invention and / or their corresponding tautomers are preferably considered to be pharmaceutically acceptable.

[0041] The term "pharmaceutically acceptable" refers to compounds (including salts), materials, compositions, and dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0042] The term "its pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxic effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in the form of its free acid or free base with a suitable base or acid, respectively. Further, pharmaceutically acceptable salts of the compounds of the present invention and / or their corresponding tautomers may be prepared in situ during further processing in the form of the free acid or free base, for example, during the manufacture of a pharmaceutical formulation.

[0043] Pharmaceutically acceptable salts include, inter alia, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011.

[0044] Pharmaceutically unacceptable salts may be used, for example, as intermediates in the preparation of the compounds of the present invention and / or their corresponding tautomers or pharmaceutically acceptable salts thereof.

[0045] Suitable pharmaceutically acceptable salts can include acid or base addition salts. Such base addition salts can be formed by reacting the compounds of the present invention and / or their corresponding tautomers (e.g., those containing acidic functional groups) with a suitable base in a suitable solvent such as an organic solvent, if necessary, to obtain a salt, which can be isolated by various methods including crystallization and filtration. Such acid addition salts can be formed by reacting the compounds of the present invention and / or their corresponding tautomers (e.g., those containing basic amines or other basic functional groups) with a suitable acid in a suitable solvent such as an organic solvent, if necessary, to obtain a salt, which can be isolated by various methods including crystallization and filtration.

[0046] The salt may be prepared in situ during the final isolation and purification of the compound of the present invention and / or its corresponding tautomer. When the basic compound of the present invention and / or its corresponding tautomer is isolated as a salt, the corresponding free base of this compound may be prepared by any suitable method known in the art, including treating the above salt with an inorganic or organic base. Similarly, when the compound of the present invention and / or its corresponding tautomer containing an acidic functional group is isolated as a salt, the corresponding free acid of this compound may be prepared by any suitable method known in the art, including treating the above salt with an inorganic or organic acid.

[0047] It will be understood that when the compound of the present invention and / or its corresponding tautomer contains two or more basic moieties, the stoichiometric amount of salt formation may include 1 equivalent, 2 equivalents or more of an acid. Such salts will include 1, 2 or more acid counterions, for example, a dihydrochloride salt.

[0048] The stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compound of the present invention and / or its corresponding tautomer are included within the scope of the present invention, for example, quasi-stoichiometric salts in which the counterion contains two or more acidic protons.

[0049] Examples of pharmaceutically acceptable acid addition salts include 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, hydrogen tartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, dicosuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edsylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisinate (2,5-dihydroxybenzoate), glucoheptonate (glseptonate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinol, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, basic acetate, succinate, sulfamate, sulfate, tartrate, theocurate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate are included, but not limited thereto.,

[0050] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolildine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinene, quinoline, sodium, strontium, t-butylamine, and zinc.,

[0051] In some embodiments, the following: [Chemical formula] (wherein, R1 is -P(O)(OH)O - M + , -PO(O - )2·2M + or -PO(O - )2·D 2+ ; and each M + is independently a pharmaceutically acceptable monovalent cation, and D 2+ is a pharmaceutically acceptable divalent cation) and is a pharmaceutically acceptable salt of a compound selected from the group consisting of

[0052] Suitable monovalent cations (M + ) for use in the present invention include, but are not limited to, alkali metal ions and ammonium ions. As used herein, the term "alkali metal" refers to Group I elements and includes, but is not limited to, lithium (Li), sodium (Na), potassium (K) and the like. When two M + are present, each M + is independently a monovalent cation and each M + can be the same or different. In some embodiments, when two M + are present, each M + is the same.

[0053] Suitable divalent cations (D 2+ ) for use in the present invention include, but are not limited to, alkaline earth metal ions and divalent aluminum ions. As used herein, the term "alkaline earth metal" refers to Group II elements and includes, but is not limited to, calcium (Ca), magnesium (Mg), strontium (Sr) and the like.

[0054] Other monovalent and divalent cations suitable for use in the present invention include monovalent or divalent ions of amino acid ions such as arginine, lysine, ornithine, and other monovalent or divalent ions. Monovalent and divalent cations containing basic nitrogen-containing groups can be prepared by quaternization using agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate).

[0055] In certain embodiments, each M + is independently an alkali metal ion. In another embodiment, each M + is independently Li + , Na + , or K + . In another embodiment, each M + is Li + . In another embodiment, each M + is Na + . In another embodiment, each M + is K + .

[0056] In certain embodiments, each M + is independently an ammonium ion. In certain embodiments, each M + is independently an ammonium ion of the formula -N(R a )4, wherein each R a is independently hydrogen, cyclohexyl, or -(C1-C6)alkyl optionally substituted by 1 to 6 -OH groups. In another embodiment, each M + is independently selected from NH4 + , ethanolamine ion

Chemical formula

[0057] In one embodiment, each D 2+ is an alkaline earth metal ion. In another embodiment, each D 2+ is Mg 2+ , Ca 2+ , or Sr 2+ . In another embodiment, each D 2+ is Mg 2+ or Ca 2+ . In another embodiment, each D 2+ is Mg 2+ . In another embodiment, each D 2+ is Ca 2+ .

[0058] In one embodiment, the following: [Chem.] (wherein: R 1 is -P(O)(OH)O - M + , -PO(O - )2·2M + , or -PO(O - )2·D 2+ ; each M + is independently a pharmaceutically acceptable monovalent cation, and D 2+ is a pharmaceutically acceptable divalent cation) provides a compound.

[0059] In one embodiment, the following: [Chem.] (wherein: R 1 is -P(O)(OH)O - M + , -PO(O -)2·2M + 、 or -PO(O - )2·D 2+ ; and each M + is independently a pharmaceutically acceptable monovalent cation, and D 2+ is a pharmaceutically acceptable divalent cation) to provide a compound that is

[0060] In certain embodiments, the following:

Chemical formula

[0061] In certain embodiments, the following:

Chemical formula

[0062] In one embodiment, the following:

Chemical formula

[0063] Solvate / Crystal / Cocrystal Many organic compounds can form complexes with solvents in the reacted solvent or form complexes by precipitation or crystallization from the reacted solvent. These complexes are known as "solvates". For example, complexes with water are known as "hydrates". Solvates may be produced using high-boiling solvents and / or solvents with a high tendency to form hydrogen bonds such as water, ethanol, iso-propyl alcohol, and N-methylpyrrolidone. Identification methods for solvates include, but are not limited to, NMR and microanalysis. The compounds of the present invention and / or their corresponding tautomers or salts thereof may exist in solvated and non-solvated forms.

[0064] The compounds of the present invention can be in crystalline or amorphous form. The most thermodynamically stable crystalline forms of the compounds of the present invention are of particular interest.

[0065] The crystalline forms of the compounds of the present invention may be characterized and identified using several conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid state nuclear magnetic resonance (ssNMR).

[0066] In one embodiment, the present invention provides a crystalline form of (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

[0067] In another embodiment, the present invention relates to CuK α A crystalline form of (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles of about 11.9, about 13.2, about 14.7 and / or about 16.0° 2θ when measured using CuK

[0068] In another embodiment, the present invention relates to CuK α A crystalline form of (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, characterized by an X-ray powder diffraction (XRPD) pattern comprising substantially the diffraction angles listed in Table 2 when measured using CuK

[0069] In a further embodiment, the present invention provides a crystalline form of (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, characterized by an X-ray powder diffraction (XRPD) pattern substantially according to FIG. 4.

[0070] Where it is shown herein that there is a peak in the XRPD pattern at a given value, this peak is normally intended to be within ±0.2, for example within ±0.1, of the cited value.

[0071] Stereoisomer The compounds of the present invention and / or their corresponding tautomers and their pharmaceutically acceptable salts may contain one or more asymmetric centers (also referred to as chiral centers) and thus may exist as individual enantiomers, diastereomers, or other stereoisomers, or mixtures thereof. Chiral centers such as chiral carbon atoms may be present in substituents such as alkyl groups. Where the stereochemistry of a chiral center present in the chemical structure of a compound of the present invention or of any of those exemplified herein is not specified, this structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, the compounds of the present invention and / or their corresponding tautomers and their pharmaceutically acceptable salts containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.

[0072] The compounds of the present invention containing one or more asymmetric centers and / or their corresponding tautomers and pharmaceutically acceptable salts thereof may be separated by methods known to those skilled in the art. For example, such separation may be carried out by (1) the formation of diastereomeric salts, complexes or other derivatives; (2) selective reaction with stereospecific reagents, for example, by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica bonded with a chiral ligand or in the presence of a chiral solvent. Those skilled in the art will understand that when the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, further steps are required to liberate it in the desired form. Alternatively, a specific stereoisomer may be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by asymmetric transformation by converting one enantiomer to another enantiomer.

[0073] Isotope The present invention also includes all appropriate isotopic variations of the compounds and / or their corresponding tautomers or pharmaceutically acceptable salts described herein. Isotopic variations of the compounds of the present invention and / or their corresponding tautomers or pharmaceutically acceptable salts are defined as those in which at least one atom is replaced by an atom having the same atomic number but a different atomic weight from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F and 36 Cl and other isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine. Specific isotopic variations of the compounds of the present invention and / or their corresponding tautomers or salts or solvates, for example, 3 H or 14Those incorporating radioisotopes such as C are useful for drug and / or substrate tissue distribution studies. Tritiation, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for facilitating their preparation and detection. Further, substitution with isotopes such as deuterium, i.e., 2 H, can result in certain therapeutic advantages obtained from greater metabolic stability, such as increased in vivo half-life or decreased required dose, and thus may be preferred in some circumstances. Isotope variations of the compounds of the present invention and / or their corresponding tautomers or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures such as the illustrative methods or preparations described in the following examples using appropriate isotope variations of appropriate reagents.

[0074] Tautomer Furthermore, the compounds of the present invention may exist as tautomers or in the form of tautomers. Any reference to a named or structurally depicted compound is to be understood as intending to encompass all tautomers of such compound. Conventionally, in the field of chemical technology, tautomers are understood to be structural or constitutional isomers of a chemical compound that readily interconvert. This reaction generally results in the rearrangement of a proton. Structural or constitutional isomers (by IUPAC) have different bonding patterns and atomic constitutions, as opposed to stereoisomers, which have the same molecular formula and where the molecular bonds are always in the same order and differ only in spatial arrangement. The concept of tautomerization is called tautomerism. The chemical reaction that interconverts the two is called tautomerization. Care should be taken not to confuse tautomers with the depiction of "contributing structures" in chemical resonance. Tautomers are different chemical species and can be identified as such by different spectroscopic data, while resonance structures are merely a convenient depiction and do not physically exist. For example, the 2-pyridone ring exhibits tautomerism, and the proton bonded to nitrogen can move to oxygen, giving the tautomer 2-hydroxypyridine.

[0075] JPEG2025519523000021.jpg23170

[0076] Pharmaceutical Composition In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a tautomer thereof, or a pharmaceutically acceptable salt thereof, described in any one of the embodiments disclosed herein, and a pharmaceutically acceptable excipient (also referred to as a carrier and / or diluent in the pharmaceutical art). An excipient is acceptable in the sense that it is compatible with the other ingredients of the formulation and not harmful to its recipient (i.e., the patient).

[0077] Pharmaceutically acceptable excipients are non-toxic and should not interfere with the effectiveness of the active ingredient. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected, the route of administration, and others. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, carriers, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweeteners, flavors, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. Examples of pharmaceutically acceptable excipients are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Company), THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (Gower Publishing Limited), and THE HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (the American Pharmaceutical Association and the Pharmaceutical Press).

[0078] The pharmaceutical composition may be adapted for administration by any suitable or preferred route, such as systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, or others. Parenteral administration usually includes intravenous, intramuscular, and subcutaneous injection or infusion by injection or infusion. Inhalation refers to administration to the patient's lungs whether inhaled through the mouth or through the nasal cavity. Usually, administration is via the oral route or via a parenteral route such as the intravenous route.

[0079] A pharmaceutical composition adapted for oral administration may be provided as a solid dosage form such as tablets, capsules, caplets, troches, pills; powders; or as a liquid dosage form such as solutions, suspensions, syrups, elixirs, or emulsions, and others. A pharmaceutical composition adapted for parenteral administration may be provided as a solution, suspension, and powder for reconstitution immediately before use.

[0080] In some embodiments, the pharmaceutical composition of the present invention is formulated for oral administration. In other embodiments, the pharmaceutical composition of the present invention is formulated for intravenous administration.

[0081] Generally, the pharmaceutical composition of the present invention is prepared using conventional materials and techniques such as mixing, compounding, and similar methods. Some of the methods commonly used in the art are described in Remington’s PHARMACEUTICAL SCIENCES (Mack Publishing Company).

[0082] Solid dosage forms such as tablets and capsules can be formulated by mixing the compound of the present invention with excipients such as diluents and fillers (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, and the like), binders (e.g., starch, acacia gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, and the like), lubricants (e.g., magnesium stearate, talc, and the like), and the like. A pharmaceutical composition adapted for parenteral administration can be an injection solution prepared from a powder, granule, or tablet by mixing with a carrier such as water for dilution, saline, and the like, and bases and the like may be used for pH adjustment.

[0083] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of the compound of the present invention and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0084] The compounds and pharmaceutical compositions of the present invention as defined herein may be administered once or according to a dosing regimen, with several doses being administered over a given period at various time intervals. For example, the dose may be administered once a day, twice a day, three times a day, or four times a day. The dose may be administered until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. The dose of the compound of the present invention may be in the range of 0.001 mg / kg to 100 mg / kg, such as 0.001 mg / kg to 50 mg / kg. Preferably, the selected dose is administered orally or parenterally.

[0085] According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising mixing (or admixing) a compound of the present invention or a tautomer or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) with at least one pharmaceutically acceptable excipient.

[0086] Synthetic Scheme and General Preparation Method The present invention also relates to a method for preparing the compounds of the present invention disclosed herein. The compounds of the present invention may be prepared by any of several methods using conventional organic synthesis as specifically illustrated by the exemplary compounds described in the schemes below and in the Examples section of this specification, or by taking advantage of the knowledge of a skilled organic chemist. Suitable synthetic routes are illustrated below in the following general reaction schemes. The synthetic procedures provided in the following schemes are applicable to the preparation of the compounds of the present invention having various different functional groups as defined using appropriate precursors.

[0087] In the preparation of the compounds of the present invention, those skilled in the art will likely consider it necessary and / or desirable to protect one or more sensitive groups in the molecule or appropriate intermediates so that unwanted side reactions do not occur. If the substituents described herein are not compatible with the synthetic methods described herein, those skilled in the art will consider that the substituents may be protected with appropriate protecting groups that are stable to the reaction conditions. The protecting groups can be removed at an appropriate point during the reaction sequence to obtain the desired intermediate or target compound. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in conventional methods. See, for example, “Protective Groups in Organic Synthesis” by T.W. Green and P.G.M Wets (Wiley & Sons, 1991) or “Protecting Groups” by P. J. Kocienski (Georg Thieme Verlag, 1994). If necessary, subsequent deprotection yields compounds of generally disclosed properties. In some cases, the substituents can be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituents to either another substituent that is useful as an intermediate compound or the desired substituent in the target compound.

[0088] The schemes shown below are representative of methods for preparing the compounds of the present invention, but these are merely intended to illustrate methods that may be used to produce the compounds of the present invention. Intermediates (compounds used in the preparation of the compounds of the present invention) may exist as salts. Thus, in connection with the intermediates, the phrase “compound of formula (number)” means a compound having this structural formula or a pharmaceutically acceptable salt thereof. Compound names were generated using the software naming program ChemDraw 5 Ultra v16.0 (available from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts, 02451, USA).

[0089] Several methods for preparing the compounds of the present invention are illustrated by the following schemes and examples. The starting materials are either commercially available or prepared by known procedures as described in the literature or exemplified.

[0090] General Synthetic Scheme

Chem.

[0091] The preparation of the compounds of the present invention generally begins with the synthesis of N-substituted-2-amino aromatic derivatives I-3 (Scheme I). Arylation of aniline nitrogen using an appropriate aryl halide can be carried out in an appropriate solvent such as 1,4-dioxane, using a transition metal catalyst such as Pd2(dba)3 or Cu / CuO, an appropriate ligand such as BINAP or Xantphos, and an inorganic base such as Cs2CO3 or K2CO3. In some cases where X = F, the conversion can be carried out by an SAr reaction in the presence of a base such as diisopropylethylamine (DIPEA) in an appropriate solvent such as dimethylformamide (DMF). N Ar reaction.

[0092] For each of the intermediates I-1, I-2, and I-3 in Scheme I, each of R1 and R2 is independently halo (e.g., -F or -Cl) or haloalkyl (e.g., -CF3); R3, when present, is phenyl which may be substituted; and R is H or alkyl.

[0093]

Chem.

[0094] The intermediate N-substituted-2-aminoaromatic acid derivative I-3 prepared as illustrated in Scheme I can be converted to II-1 by coupling the appropriate aryl-NH2, e.g., 2-methoxy-4-aminopyridine, with I-3 under various amide coupling conditions known to those skilled in the art (Scheme II). For example, in a suitable solvent, usually DMF, DMA or acetonitrile, in the presence of an amine base such as triethylamine or Hunig's base (diisopropylethylamine), a standard coupling reagent such as EDC / HOBT, HATU, HBTU or T3P may be used. Alternatively, the acid can be converted to the corresponding acid chloride using a reagent such as thionyl chloride or oxalyl chloride, and then this acid chloride can be reacted with the appropriate aryl-NH2 (such as 2-methoxy-4-aminopyridine) in the presence of an acid scavenger or a base such as pyridine, 2,6-lutidine, triethylamine or Hunig's base in a suitable solvent such as dichloromethane or pyridine to obtain the desired coupling product II-1. The formation of the dihydroquinazolinone ring system as in II-2 involves the reaction of II-1 with formaldehyde or a suitable equivalent. For example, the reaction may be carried out using gaseous formaldehyde, paraformaldehyde, or formaldehyde as s-trioxane in the presence of an acid, preferably PTSA or sulfuric acid. Alternatively, the dihydroquinazolinone ring system can be generated by the reaction of II-1 using diiodomethane or chloroiodomethane as a formaldehyde equivalent. In this variant of the cyclization reaction, a base, usually Cs2CO3 or NaH, may also be used in a suitable solvent, often acetonitrile or DMF. The choice of using formaldehyde or diiodomethane depends on the specific reaction characteristics of the substrate II-1.

[0095] In each of intermediates I-3, II-1, and II-2 in Scheme II, each of R1 and R2 is independently halo (e.g., -F or -Cl) or haloalkyl (e.g., -CF3); R3 is optionally substituted phenyl; and each of R4 and R5 is independently hydrogen or -CH3.

[0096]

Chemical formula

[0097] In variations of the methods described in Schemes I and II, the compounds can be prepared as illustrated in Scheme III. For the activated 2-halo acid (III-1; X1 = Cl, Br or I), in a suitable solvent such as 1,4-dioxane, toluene or 2-ethoxyethanol, in the presence of a catalyst such as Pd2(dba)3 or Cu / CuO, a suitable ligand such as BINAP or Xantphos, and an inorganic base, usually Cs2CO3 or K2CO3, III-2 can be obtained using a reaction with a suitable aniline or amine nucleophile at an elevated temperature, either by standard heating or microwave irradiation. In some cases where X1 = F, in a suitable solvent such as DMF, in the presence of a base such as DIPEA, the conversion may be carried out by S N Ar reaction. The conversion of III-2 to III-3 and finally III-4 can be obtained as described in Scheme II.

[0098] In each of intermediates III-1, III-2, III-3, and III-4 in Scheme III, each of R1 and R2 is independently halo (e.g., -F or -Cl) or haloalkyl (e.g., -CF3); R3, when present, is optionally substituted phenyl; each of R4 and R5 is independently hydrogen or -CH3; and X is CH or N.

[0099]

Chemical formula

[0100] As shown in Scheme IV, the conversion of compound III-4 to pyridone IV-1 can be carried out by reacting compound III-4 with a mixture of TMS-chloride and NaI, or a solution of TMS-iodide, in a neutral solvent such as acetonitrile at elevated temperature. Compound IV-1 can be reacted with chloromethyl chloroformate in a suitable solvent such as EtOAc and DMF in the presence of an organic base such as DABCO to obtain chloromethyl pyridone IV-2. Compound IV-3 can be obtained by reacting compound IV-2 with di-tert-butyl phosphate in the presence of a phase transfer catalyst such as TBAI in the solvent DMF at elevated temperature. The prodrug compound of the present invention can be obtained by removing the tert-butyl protecting group under acidic conditions such as acetic acid in acetonitrile and water.

[0101] In each of intermediates III-4, IV-1, IV-2, IV-3, and IV-4 in Scheme IV, each of R1 and R2 is independently halo (e.g., -F or -Cl) or haloalkyl (e.g., -CF3); R3 is optionally substituted phenyl; each of R4 and R5 is independently hydrogen or -CH3; and X is CH or N.

[0102] Method / Use In general, the present invention also relates to the use of the compounds and / or pharmaceutical compositions described herein for use as a medicament or in therapy.

[0103] The compounds of the present invention as defined herein are inhibitors of voltage-dependent sodium ion channels, and in particular the voltage-dependent sodium ion channel Na v 1.8. The activity of the compounds utilized in the present invention as inhibitors of Na v 1.8 can be assayed according to the methods generally described in the examples herein or methods available to those skilled in the art.

[0104] In one aspect, the present invention relates to the use of the compounds and pharmaceutical compositions described herein as inhibitors of voltage-dependent sodium ion channels, specifically Na v 1.8.

[0105] In certain embodiments, the present invention is a method of inhibiting a voltage-dependent sodium ion channel in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein. In another embodiment, the voltage-dependent sodium ion channel is Na v 1.8.

[0106] In certain embodiments, the present invention relates to a compound of the invention or a pharmaceutical composition of the invention for use in inhibiting a voltage-dependent sodium ion channel. In another embodiment, the voltage-dependent sodium ion channel is Na v 1.8.

[0107] In certain embodiments, the present invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting a voltage-dependent sodium ion channel. In another embodiment, the voltage-dependent sodium ion channel is Na v 1.8.

[0108] Without wishing to be bound by any particular theory, the compounds and compositions of the present invention are particularly useful for treating diseases, conditions, or disorders in which activation or overactivity of Na v 1.8 is involved. In certain diseases, conditions, or disorders in which activation or overactivity of Na v 1.8 is involved, said diseases, conditions, or disorders may also be referred to as Na v 1.8-mediated diseases, conditions, or disorders. Exemplary Na v 1.8-mediated diseases, conditions, or disorders include pain and pain-related disorders, as well as heart diseases such as atrial fibrillation.

[0109] According to embodiments of the present invention, a pain-related disease is pain caused by any one of various diseases of various etiologies described throughout this disclosure. In some embodiments, the pain and pain-related diseases are neuropathic pain, chronic pain, acute pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, cancer pain, breakthrough pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, or incontinence.

[0110] In some embodiments, the pain and pain-related diseases are neuropathic pain or chronic neuropathic pain. In some embodiments, the pain and pain-related diseases are neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, or polyneuropathy.

[0111] In some embodiments, the pain and pain-related diseases are neuropathic pain selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, posttraumatic pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, nerve crush injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache.

[0112] In some embodiments, the pain and pain-related disorders are neuropathic pain or chronic neuropathic pain selected from diabetic peripheral neuropathy, pain caused by neuropathy, nerve injury or neuron injury, pain-related nerve injury, neuralgia and related acute or chronic pain, postherpetic neuralgia, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome, central pain syndrome caused by lesions at the level of the nervous system, traumatic nerve injury, nerve compression or nerve entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia, HIV sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0113] In some embodiments, the pain and pain-related disorders are visceral pain, and the visceral pain is inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0114] In some embodiments, the pain and pain-related disorders are musculoskeletal pain, and the musculoskeletal pain is osteoarthritis, back pain, cold pain, burning pain or toothache.

[0115] In some embodiments, the pain and pain-related disorders are breakthrough pain, and the breakthrough pain is fibromyalgia.

[0116] In some embodiments, the pain and pain-related disorders are chronic or acute pre-operative related pain or chronic or acute post-operative related pain. Post-operative related pain includes outpatient post-operative pain. Ambulatory surgery, also known as outpatient surgery, represents same-day surgery that does not require an overnight stay in a hospital or other medical facility. In some embodiments, the pain and pain-related disorders are selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthralgia, toothache or inflammatory pain. In some embodiments, the post-operative related pain is selected from pain after aponeurotoma resection, pain after hernia repair, pain after thoracic surgery or pain after cosmetic surgery.

[0117] In some embodiments, the pain and pain-related disorders are pain caused by mental trauma or iatrogenic medical or dental procedures. As used herein, the term "iatrogenic" refers to pain inadvertently induced by medical or dental practitioners, such as surgeons or dentists, during medical or dental treatment or preventive procedures, including preoperative (i.e., "before surgery"), intraoperative (i.e., pain induced during surgery or during medical treatment during non-surgical or surgical treatment), and postoperative (i.e., pain after surgery, postoperative, or surgically induced) medical or dental procedures, but is not limited thereto.

[0118] In some embodiments, the pain and pain-related disorders are nociceptive pain, and the nociceptive pain is postoperative pain, cancer pain, back pain and craniofacial pain, osteoarthritis pain, toothache, or diabetic peripheral neuropathy.

[0119] In some embodiments, the pain and pain-related disorders are inflammatory pain. Inflammatory pain can be pain of various physiological origins. In some embodiments, the inflammatory pain is selected from pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disorders, tendosynovitis and gout, shoulder tendinitis or bursitis, gouty arthritis, and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic joint pain and related neuralgia, or acute pain. In some embodiments, the inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, and juvenile arthritis. In some embodiments, the inflammatory pain is selected from rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, juvenile arthritis, rheumatic disorders, gout, shoulder tendinitis or bursitis, polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic or acute pain, and related neuralgia. In some embodiments, the inflammatory pain is rheumatoid arthritis or vulvodynia.

[0120] In some embodiments, the inflammatory pain is osteoarthritis, chronic degenerative joint pain (e.g., hip or knee) or chronic inflammatory demyelinating polyneuropathy.

[0121] In some embodiments, the pain and pain-related disorders are musculoskeletal pain. In some embodiments, the musculoskeletal pain is selected from bone pain and joint pain, osteoarthritis, low back pain and neck pain, and pain resulting from physical trauma or amputation. In some embodiments, the musculoskeletal pain is selected from bone pain and joint pain, osteoarthritis (e.g., knee, hip), tendinitis (e.g., shoulder), bursitis (e.g., shoulder), low back pain and neck pain, sprains, strains, and pain resulting from physical trauma or amputation.

[0122] In some embodiments, the pain and pain-related disorders are neuropathies, nerve injury-related pain, nerve root avulsion injury-related pain, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome, central pain syndrome caused by lesions at the level of the nervous system, traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy, or pain disorders associated with or resulting from nerve or neuron injury caused by diseases selected therefrom.

[0123] In some embodiments, the pain and pain-related disorders are pain caused by trauma, or pain caused by iatrogenic, medical, or dental procedures.

[0124] In some embodiments, the pain and pain-related disorders are myofascial pain, myositis or muscle inflammation, repetitive motion pain, complex regional pain syndrome, sympathetically maintained pain, cancer, pain associated with toxins and chemotherapy, postoperative pain syndrome and / or related phantom limb pain, pain of postoperative medical or dental procedures or treatments, or pain associated with HIV or induced by HIV treatment.

[0125] In some embodiments, the pain and pain-related disorders are neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuropathy (SFN), paroxysmal extreme pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neurogenic back pain, sciatica, non-specific pain, pain in multiple sclerosis, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, vulvodynia, pain due to physical trauma, pain after amputation, neuropathic pain, phantom limb pain, cancer, toxins, and other pain-related diseases that are neuropathic pain selected from chronic inflammatory conditions.

[0126] In some embodiments, the pain and pain-related disorders are acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety disorders, depressive disorders, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, headache, neck pain, neuralgia, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility abnormalities.

[0127] In some embodiments, the pain and pain-related disorders are femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache, migraine, tension headache (including cluster headache), chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal secretions, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom limb pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendinitis, injury / sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammation, burn and trauma pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell disease, acute pancreatitis, protrusion pain, oral and facial pain including sinusitis pain, toothache, pain in multiple sclerosis (MS), pain in depression, Hansen's disease pain, Behçet's disease pain, painful lipodystrophy, phlebitis pain, pain associated with Guillain-Barré syndrome, painful leg and moving toes, Haglund's syndrome, erythromelalgia, Fabry's disease pain, bladder and urogenital diseases including urinary incontinence, frequent urination of the bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) (type I and type II), widespread pain, paroxysmal extreme pain disorder, psychogenic pruritus, tinnitus, or angina-induced pain.

[0128] In another aspect, the present invention relates to methods for treating heart diseases including atrial fibrillation and arrhythmia and the use of the compounds and pharmaceutical compositions of the present invention in pharmaceuticals.

[0129] In some embodiments, the heart disease is atrial fibrillation caused by a natural onset or a disease as defined herein. The atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease. In certain embodiments, the atrial fibrillation is selected from paroxysmal, persistent, and long-term atrial fibrillation.

[0130] In some embodiments, the heart disease includes arrhythmia.

[0131] Accordingly, in another aspect, the present invention also provides a method of treatment in a subject, particularly a human. Disease states that can be treated by the methods and compositions provided herein include, but are not limited to, pain and pain-related diseases, and heart diseases.

[0132] The term "treatment" refers to alleviating a particular pathological condition, removing or reducing one or more symptoms of the pathological condition, slowing or removing the progression of the pathological condition, and delaying the recurrence of the pathological condition in a previously affected patient or subject.

[0133] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. The term "therapeutically effective amount" refers to the amount of a compound of the present invention or its compatibility, or a pharmaceutically acceptable salt thereof, that elicits a desired biological response in the human body. This can vary depending on the compound, the disease and its severity, and the age and weight of the subject being treated.

[0134] The term "subject" refers to the human body.

[0135] In one aspect, the present invention relates to a method of treating pain or a pain-related disease as defined herein in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0136] In one embodiment, there is provided a method for treating acute pain or chronic pain in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0137] In one embodiment, there is provided a method for treating pain caused by trauma, pain caused by iatrogenic medical or dental procedures, or pre- or post-operative related pain in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0138] In one embodiment, there is provided a method for treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, or breakthrough pain in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0139] In one embodiment, there is provided a method for treating neuropathic pain or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0140] In one embodiment, there is provided a method for treating inflammatory pain selected from the group consisting of osteoarthritis, chronic osteoarthralgia, and chronic inflammatory demyelinating polyneuropathy in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0141] In one embodiment, there is provided a method for treating pain or pain-related disorders selected from the group consisting of neuropathic pain, postoperative pain in the outpatient setting, and osteoarthritis in a human in need of treatment, the method comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein. In some embodiments, the pain and pain-related disorders are neuropathic pain. In some embodiments, the pain and pain-related disorders are chronic neuropathic pain. In some embodiments, the pain and pain-related disorders are small fiber neuropathy. In some embodiments, the pain and pain-related disorders are postoperative pain in the outpatient setting. In some embodiments, the pain and pain-related disorders are osteoarthritis. In some embodiments, the pain and pain-related disorders are knee osteoarthritis and / or hip osteoarthritis.

[0142] In another aspect, the invention provides a compound of the invention and a pharmaceutical composition of the invention as described herein for use in the treatment of pain or pain-related disorders as defined herein.

[0143] In one embodiment, there are provided a compound of the invention and a pharmaceutical composition of the invention for use in the treatment of acute or chronic pain.

[0144] In one embodiment, there are provided a compound of the invention and a pharmaceutical composition of the invention for use in the treatment of pain caused by trauma, pain caused by iatrogenic medical or dental procedures, or preoperative or postoperative related pain.

[0145] In one embodiment, there are provided a compound of the invention and a pharmaceutical composition of the invention for use in the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or iatrogenic pain.

[0146] In certain embodiments, provided are the compounds of the present invention and pharmaceutical compositions of the present invention for use in the treatment of neuropathic pain or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0147] In certain embodiments, provided are the compounds of the present invention and pharmaceutical compositions of the present invention for use in the treatment of inflammatory pain selected from the group consisting of osteoarthritis, chronic degenerative joint pain, and chronic inflammatory demyelinating polyneuropathy.

[0148] In certain embodiments, provided are the compounds of the present invention and pharmaceutical compositions of the present invention for use in the treatment of pain or pain-related disorders selected from the group consisting of neuropathic pain, postoperative pain in the outpatient setting, and osteoarthritis. In some embodiments, the pain and pain-related disorders are neuropathic pain. In some embodiments, the pain and pain-related disorders are chronic neuropathic pain. In some embodiments, the pain and pain-related disorders are small fiber neuropathy. In some embodiments, the pain and pain-related disorders are postoperative pain in the outpatient setting. In some embodiments, the pain and pain-related disorders are osteoarthritis. In some embodiments, the pain and pain-related disorders are knee osteoarthritis and / or hip osteoarthritis.

[0149] In another aspect, the present invention also provides the use of the compounds of the present invention and the pharmaceutical compositions of the present invention described herein in the manufacture of a medicament for the treatment of the pain and pain-related disorders described herein.

[0150] In certain embodiments, provided is the use of the compounds of the present invention and the pharmaceutical compositions of the present invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0151] In certain embodiments, provided is the use of a compound of the invention and a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain caused by trauma, pain caused by iatrogenic medical or dental procedures, or preoperative or postoperative related pain.

[0152] In certain embodiments, provided is the use of a compound of the invention and a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or iatrogenic pain.

[0153] In certain embodiments, provided is the use of a compound of the invention and a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0154] In certain embodiments, provided is the use of a compound of the invention and a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of inflammatory pain selected from the group consisting of osteoarthritis, chronic osteoarthralgia, and chronic inflammatory demyelinating polyneuropathy.

[0155] In certain embodiments, provided is the use of a compound of the invention and a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain or pain-related disorders selected from the group consisting of neuropathic pain, postoperative pain in the outpatient setting, and osteoarthritis. In some embodiments, the pain and pain-related disorders are neuropathic pain. In some embodiments, the pain and pain-related disorders are chronic neuropathic pain. In some embodiments, the pain and pain-related disorders are small fiber neuropathy. In some embodiments, the pain and pain-related disorders are postoperative pain in the outpatient setting. In some embodiments, the pain and pain-related disorders are osteoarthritis. In some embodiments, the pain and pain-related disorders are knee osteoarthritis and / or hip osteoarthritis.

[0156] In one aspect, the present invention relates to a method for treating atrial fibrillation as defined herein in a human in need of treatment, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0157] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of atrial fibrillation. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0158] In another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention as described herein in the manufacture of a medicament for the treatment of atrial fibrillation. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0159] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in therapy.

[0160] Combination Therapy The compounds and pharmaceutical compositions of the present invention disclosed herein can be used in combination or co-administered with other therapeutic agents, in particular agents that can enhance the activity or pharmacokinetic profile of the compounds. The combination therapy according to the present invention comprises the administration of at least one compound of the present invention and the use of at least one other therapeutic method comprising the administration of one or more other therapeutic agents.

[0161] As used herein, the terms "co-administer" and derivatives thereof refer to the Na of the present invention described hereinv 1.8 represents either the simultaneous administration of the inhibitory compound and an additional active ingredient or any method of separate sequential administration. The additional active ingredient, when administered to a human in need of treatment, includes any compound or therapeutic agent known or showing advantageous properties. Usually, when the administrations are not simultaneous, the compounds are administered at times close to each other. Further, the compounds may be administered in the same or separate dosage forms, for example, one compound may be administered orally and another compound may be administered intravenously.

[0162] Other therapeutic agents that may be used in combination with the compounds of the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, Nav1.7 inhibitors, Nav1.9 inhibitors, antidepressants (i.e., but not limited to, duloxetine or amitriptyline, etc.), antiepileptic drugs (i.e., but not limited to, pregabalin and gabapentin, etc.), opioid agents (i.e., but not limited to, hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, and the like, etc.), and others; the above administrations are also determined by those skilled in the art respectively. In one aspect, suitable Nav1.7 inhibitors or Nav1.9 inhibitors for use in the present invention include, but are not limited to, Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0163] Each component of the combination used for therapeutic purposes (e.g., the compound or pharmaceutical composition of the present invention and an additional therapeutic agent) may be administered orally, intravenously or parenterally or a combination thereof. Each component of the therapeutic combination may be administered by simultaneous administration, co-administration, or sequential administration; and / or by the same or different routes of administration or a combination of routes of administration, but is not limited thereto. In certain embodiments, each of the same or different routes of administration or a combination of routes of administration is selected from oral, intravenous and parenteral administration.

Examples

[0164] The following examples illustrate the present invention. These examples are not intended to limit the scope of the invention, but rather are intended to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. While specific aspects or embodiments of the invention are described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0165] Synthetic Example Those skilled in the art will understand that purification methods (using acidic or basic modifiers) or compound work-up procedures (using acidic or basic conditions) can result in the formation of salts of the title compound (e.g., hydrobromide, formate, hydrochloride, trifluoroacetate, or ammonium salts of the title compound). The present invention is intended to encompass such salts.

[0166] The final compounds are characterized by GCMS and LCMS (conditions listed below) as well as NMR. 1 1H NMR or 19 19F NMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, a Bruker Avance 400 MHz spectrometer, and a Varian Mercury Plus-300 MHz spectrometer. CDCl3 is deuterated chloroform, DMSO-d6 is hexadeuterodimethylsulfoxide, and CD3OD is tetradeuteromethanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or from the NMR solvent. The abbreviations for NMR data are as follows: s = singlet, d = doublet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J is the NMR coupling constant measured in Hertz.

[0167] HPLC method: Method A:UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column), using a gradient of 1 - 100% MeCN / H2O / 0.1% TFA over 1.85 minutes at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS with positive ESI. Method B: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column), using a gradient of 1 - 100% MeCN / H2O / 0.1% 10 mM ammonium bicarbonate in water adjusted to pH 10 with 25% ammonium hydroxide solution over 1.85 minutes at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS with positive ESI.

[0168] In the description of the following experiments, the following abbreviations may be used.

Table 1

[0169] Example 1: Dihydrogen phosphate (5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl Project A: 3-(1-(Chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-fluoro-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one [Chemical formula]

[0170] A solution of 7-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (which may be synthesized as described in Example 107 of International Publication No. WO 2020 / 261114) (6.73 g, 14.98 mmol) and DABCO (2.52 g, 22.46 mmol) in ethyl acetate (140.0 ml) and N,N-dimethylformamide (DMF) (14.00 ml) was added dropwise with chloromethyl chloroformate (4.00 ml, 44.9 mmol), and immediately a white precipitate formed. The reaction mixture was heated at 85 °C for 18 h. Additional chloromethyl chloroformate (2.66 ml, 30.0 mmol) was added and the reaction was heated for an additional 3 h. Additional DABCO (0.420 g, 3.74 mmol) and chloromethyl chloroformate (2.66 ml, 30.0 mmol) were added again and the reaction was heated for an additional 19 h. Then, chloromethyl chloroformate (1.332 ml, 14.98 mmol) was added and the reaction was heated for 4 h. The reaction mixture was cooled, diluted with more EtOAc, quenched with water and stirred for 10 min. The solid was filtered, washed with water to give 3.90 g of the desired product as a bright yellow solid. The filtrate layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was triturated with DCM to give a light brown solid which was further triturated with water to give an additional 1.8 g of the desired product as an off-white solid. The two solids were combined to give 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-fluoro-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (5.71 g, 11.01 mmol, 73.5% yield). HPLC / MS 1.24 min (Method B), [M+H] + 498.0。 1 H NMR (DMSO-d 6,400 MHz) δ 8.10 (d, 1H, J = 7.8 Hz), 7.4 - 7.6 (m, 2H), 7.3 - 7.4 (m, 1H), 7.2 - 7.2 (m, 1H), 6.4 - 6.5 (m, 1H), 5.6 - 6.4 (m, 3H), 4.8 - 5.6 (m, 2H), 2.4 - 2.5 (m, 3H), 2.2 - 2.3 (m, 3H).

[0171] Process B: Di-tert-butyl phosphate ((5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl)

Chemical Structure

[0172] To a solution of 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-fluoro-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (6.20 g, 12.45 mmol) and potassium di-tert-butyl phosphate (4.64 g, 18.68 mmol) in N,N-dimethylformamide (DMF) (170 ml) was added tetrabutylammonium iodide (0.460 g, 1.245 mmol). The reaction mixture was heated at 70 °C for 3 hours, and a gel formed. The reaction mixture was cooled and quenched with water, and a precipitate formed. The solid was filtered and washed with water to give di-tert-butyl phosphate ((5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) as a bright yellow solid (7.24 g, 10.24 mmol, 82% yield). HPLC / MS 1.36 min (Method B), [M + H] + 672.2. 11H NMR (DMSO-d6, 400 MHz) δ 8.10 (d, 1H, J = 8.3 Hz), 7.4 - 7.5 (m, 2H), 7.3 - 7.4 (m, 1H), 7.2 - 7.3 (m, 1H), 6.4 - 6.4 (m, 1H), 6.14 (dd, 1H, J = 12.7, 18.1 Hz), 5.7 - 5.9 (m, 2H), 4.7 - 5.6 (m, 2H), 2.3 - 2.4 (m, 3H), 2.2 - 2.3 (m, 3H), 1.41 (s, 18H).

[0173] Step C: Dihydrogen phosphate (5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl

Chemical Structure

[0174] A slurry of di-tert-butyl phosphate ((5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (7.20 g, 10.18 mmol) in acetone (70 mL) and water (56.0 mL) was heated at 50 °C for 6 h (clear solution). The reaction mixture was allowed to come to room temperature and stirred for a further 20 h. The volatile compounds were evaporated in vacuo at 35 °C and the aqueous portion was lyophilized to give an off-white solid which was triturated with DCM:ether (1:3) to give dihydrogen phosphate (5-(7-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl as an off-white solid (5.10 g, 8.66 mmol, 85% yield). HPLC / MS 0.78 min (Method B), [M+H] + 560.2. 11H NMR (methanol-d4, 400 MHz) δ 8.25 (d, 1H, J = 7.8 Hz), 7.5 - 7.6 (m, 1H), 7.4 - 7.4 (m, 1H), 7.2 - 7.3 (m, 1H), 7.1 - 7.2 (m, 1H), 6.53 (d, 1H, J = 9.8 Hz), 6.1 - 6.2 (m, 1H), 5.99 (d, 2H, J = 6.8 Hz), 4.8 - 5.6 (m, 2H), 2.5 - 2.6 (m, 3H), 2.3 - 2.4 (m, 3H); 1 1H NMR (DMSO-d6, 400 MHz) δ 8.10 (d, 1H, J = 8.3 Hz), 7.4 - 7.5 (m, 2H), 7.3 - 7.4 (m, 1H), 7.2 - 7.3 (m, 1H), 6.4 - 6.4 (m, 1H), 6.14 (dd, 1H, J = 13.0, 18.3 Hz), 5.7 - 5.8 (m, 2H), 4.7 - 5.6 (m, 2H), 2.3 - 2.4 (m, 3H), 2.2 - 2.3 (m, 3H) (two OH protons are hidden).

[0175] Example 2: (3,6-dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate Step A: 2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinic acid

Chemical Structure

[0176] To a mixture containing 2-methyl-4-(trifluoromethoxy)aniline (4.24 g, 22.17 mmol) in water (50 mL) were added 2-chloro-5-(trifluoromethyl)nicotinic acid (5 g, 22.17 mmol), p-TsOH (1.265 g, 6.65 mmol) and pyridine (1.793 mL, 22.17 mmol). The reaction mixture was heated at 95 °C for 4 days. The reaction mixture was cooled to room temperature and then diluted with 150 mL of water and stirred for 1 hour. The solid was filtered, washed with water (3 × 25 mL) and dried in vacuo to give 2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinic acid (6.886 g, 17.20 mmol, 78% yield) as an orange-yellow solid. HPLC / MS 0.93 min (Method B), [M+H] + 381.0。 1 H NMR (DMSO-d6, 400 MHz) δ 14.16 (br s, 1H), 10.55 (s, 1H), 8.69 (dd, 1H, J = 1.0, 2.4 Hz), 8.42 (d, 1H, J = 2.4 Hz), 8.15 (d, 1H, J = 9.3 Hz), 7.32 (s, 1H), 7.24 (dd, 1H, J = 2.2, 9.0 Hz), 2.32 (s, 3H).

[0177] Step B: N-(6-methoxy-2,5-dimethylpyridin-3-yl)-2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinamide

Chem.

[0178] A solution of 2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinic acid (4.95 g, 12.37 mmol) in N,N-dimethylformamide (DMF) (60 ml) was added with 6-methoxy-2,5-dimethylpyridin-3-amine (1.882 g, 12.37 mmol), HATU (5.64 g, 14.84 mmol), and DIEA (6.48 ml, 37.1 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with water (110 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was triturated with DCM to afford 3.9 g of the desired product as an off-white solid. The mother liquor was concentrated and purified by silica gel chromatography (CombiFlash, 120 g column) using 0 - 15% EtOAc / heptane as the eluent to afford an additional 2.1 g of the desired product as an off-white solid. The two batches were combined, dissolved in EtOAc, and concentrated to afford N-(6-methoxy-2,5-dimethylpyridin-3-yl)-2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinamide (6.1 g, 11.86 mmol, 96% yield) as an off-white solid. HPLC / MS 1.57 min (Method A), [M + H] + 515.1。 1 H NMR (DMSO-d6, 400 MHz) δ 10.87 (s, 1H), 10.42 (s, 1H), 8.67 (s, 2H), 8.19 (d, 1H, J = 8.8 Hz), 7.48 (s, 1H), 7.3 - 7.3 (m, 1H), 7.23 (br d, 1H, J = 8.8 Hz), 3.90 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H).

[0179] Step C: 3-(6-methoxy-2,5-dimethylpyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one

Chemical Structure

[0180] To a solution of N-(6-methoxy-2,5-dimethylpyridin-3-yl)-2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinamide (8.1 g, 15.75 mmol) in acetonitrile (110 ml) were added cesium carbonate (20.52 g, 63.0 mmol) and diiodomethane (5.08 ml, 63.0 mmol). The reaction mixture was heated at 90 °C for 46 h, cooled to room temperature, and the resulting solid was filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (CombiFlash, 220 g column) using 0 - 20% EtOAc / heptane as eluent to give 3-(6-methoxy-2,5-dimethylpyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (5.0 g, 8.74 mmol, 55.5% yield) as a yellow solid. HPLC / MS 1.48 min (Method B), [M+H] + 527.2。 1 H NMR (DMSO-d6, 400 MHz) δ 8.62 (d, 1H, J = 1.5 Hz), 8.34 (d, 1H, J = 2.4 Hz), 7.4 - 7.5 (m, 3H), 7.31 (br d, 1H, J = 8.3 Hz), 5.0 - 5.8 (m, 2H), 3.89 (s, 3H), 2.30 (br s, 3H), 2.25 (s, 3H), 2.12 (s, 3H).

[0181] Step D: 3-(2,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one

Chemical Structure

[0182] To a solution of 3-(6-methoxy-2,5-dimethylpyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (4.9 g, 8.56 mmol) in isopropanol (100 mL) was added HCl (5 - 6N IPA solution) (42.8 mL, 214 mmol). The reaction mixture was heated at 90 °C for 3 hours, cooled, and concentrated. The residue was dissolved in EtOAc and neutralized with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (CombiFlash, 120 g column) using 0 - 10% MeOH / DCM as the eluent to give 3-(2,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (4.18 g, 8.16 mmol, 95% yield) as an off-white solid. HPLC / MS 1.14 min (method B), [M+H] + 513.1。 1 H NMR (DMSO-d6, 400 MHz) δ 11.73 (s, 1H), 8.60 (d, 1H, J = 2.0 Hz), 8.31 (d, 1H, J = 2.0 Hz), 7.4 - 7.5 (m, 2H), 7.3 - 7.3 (m, 2H), 4.9 - 5.7 (m, 2H), 2.24 (s, 3H), 2.10 (br s, 3H), 1.94 (s, 3H).

[0183] Step E: 3-(1-(Chloromethyl)-2,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one

Chem.

[0184] A solution of 3-(2,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3.82 g, 7.45 mmol) and DABCO (1.254 g, 11.18 mmol) in ethyl acetate (60 ml) and N,N-dimethylformamide (DMF) (7 ml) was added dropwise a solution of chloromethyl chloroformate (2.65 ml, 29.8 mmol) in ethyl acetate (10 ml), and a white precipitate formed. The reaction mixture was heated at 85 °C for 19 h, then further chloromethyl chloroformate (1.326 ml, 14.91 mmol) was added and stirred at 85 °C for an additional 3 h, then further chloromethyl chloroformate (0.331 ml, 3.73 mmol) was added and stirred at 85 °C for an additional 1 h. The reaction mixture was cooled, then diluted with more EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (CombiFlash, 80 g column) eluting with 100% heptane for 5 min to give 3-(1-(chloromethyl)-2,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one as a white solid (4.0 g, 7.13 mmol, 96% yield). HPLC / MS 1.31 min (Method B), [M+H] + 561.1。 1 H NMR (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 8.32 (d, 1H, J = 2.4 Hz), 7.4 - 7.5 (m, 3H), 7.31 (br d, 1H, J = 8.3 Hz), 4.9 - 6.4 (m, 4H), 2.41 (s, 3H), 2.24 (s, 3H), 2.0 - 2.0 (m, 3H).

[0185] Project F: Di-tert-butyl phosphate ((3,6-dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl)

Chem.

[0186] To a solution of 3-(1-(chloromethyl)-2,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (4.4 g, 7.84 mmol) and dipotassium di-tert-butyl phosphate (2.92 g, 11.77 mmol) in N,N-dimethylformamide (DMF) (110 ml) was added tetrabutylammonium iodide (0.290 g, 0.784 mmol), and the mixture was heated at 70 °C for 3 h. The reaction mixture was cooled and quenched with water (300 ml) to give a white precipitate. The slurry was stirred vigorously for 1 h. The solid was filtered and washed with water to give di-tert-butyl phosphate ((3,6-dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl) (5.086 g, 6.72 mmol, 86% yield). HPLC / MS 1.41 min (Method B), [M+H] + 735.1。 1 H NMR (DMSO-d6, 400 MHz) δ 8.61 (br s, 1H), 8.32 (d, 1H, J = 2.4 Hz), 7.4 - 7.5 (m, 3H), 7.31 (br d, 1H, J = 7.8 Hz), 5.84 (br d, 2H, J = 5.9 Hz), 4.8 - 5.7 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 2.00 (br s, 3H), 1.41 (s, 18H).

[0187] Project G: (3,6-Dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate

Chemical formula

[0188] A slurry of di-tert-butyl phosphate ((3,6-dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl) in acetone (50 mL) and water (40 mL) was heated at 50 °C for 26 h. The clear reaction mixture was cooled and concentrated at 50 °C under reduced pressure and dried overnight at 45 °C in a vacuum desiccator to give 4.2 g of an off-white glassy solid. The solid was triturated with ether to give 3.4 g of a white solid, which was triturated again with DCM:ether (1:2) to give (3,6-dimethyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate as a white solid (3.10 g, 4.83 mmol, 71% yield). HPLC / MS 0.78 min (Method B), [M+H] + 623.0。 1 H NMR (DMSO-d6, 400 MHz) δ 8.61 (br s, 1H), 8.32 (d, 1H, J = 2.0 Hz), 7.4 - 7.5 (m, 3H), 7.32 (br d, 1H, J = 8.3 Hz), 5.7 - 5.8 (m, 2H), 4.9 - 5.7 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 2.00 (br s, 3H) (two OH protons are hidden); 11H NMR (methanol-d4, 400 MHz) δ 8.5 - 8.5 (m, 2H), 7.4 - 7.5 (m, 2H), 7.34 (s, 1H), 7.26 (br d, 1H, J = 7.8 Hz), 6.01 (br d, 2H, J = 6.8 Hz), 4.9 - 5.7 (m, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H).

[0189] Example 3: (5-(3,4-difluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate Step A: 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroxypyrido[3,4-d]pyrimidin-4(1H)-one [Chemical formula]

[0190] A solution of 1-(1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroxypyrido[3,4-d]pyrimidin-4(1H)-one (0.162 g, 0.360 mmol) and DABCO (0.032 g, 0.288 mmol) in ethyl acetate (3.27 ml) and DMF (0.327 ml) under nitrogen was added dropwise with chloromethyl chloroformate (0.080 ml, 0.899 mmol), and the mixture was stirred at room temperature for 2 hours and then at 60 °C for 18 hours. Further chloromethyl chloroformate (0.056 ml, 0.719 mmol) and DABCO (0.032 g, 0.288 mmol) were added, and the reaction was heated for 2 hours. Further chloromethyl chloroformate (0.278 ml, 3.60 mmol) was added, and heating was continued for 18 hours. The reaction was cooled and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with water, brine, dried over MgSO4, and the solvent was concentrated. The residue was purified by flash column chromatography (Isco, 24 g column, 0 - 50% (3:1 EtOAc:EtOH) / heptane) to give the title compound (110 mg, 0.221 mmol, 61% yield). 1 H NMR (DMSO-d6, 501 MHz): δ (ppm) 8.02 - 8.06 (m, 1H, H-12), 7.84 - 8.00 (m, 1H, H-9), 7.41 - 7.58 (m, 2H, H-5, 17), 7.36 (br d, J = 18.4 Hz, 1H, H-6), 6.44 (d, J = 9.8 Hz, 1H, H-18), 5.57 - 6.32 (m, 2H, H-20), 4.85 - 5.56 (m, 2H, H-15), 2.31 - 2.48 (m, 3H, H-21), 2.23 (s, 3H, H-1). MS (m / z) 499 (M+H + )。

[0191] Step B: Di-tert-butyl phosphate ((5-(1-(3,4-difluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) [Chemical formula]

[0192] To a solution of 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroxypyrido[3,4-d]pyrimidin-4(1H)-one (0.091 g, 0.182 mmol) and dipotassium di-tert-butyl phosphate (0.068 g, 0.274 mmol) in DMF (0.91 ml) was added tetrabutylammonium iodide (6.74 mg, 0.018 mmol), and the mixture was heated at 70 °C for 2 h. Since the reaction mixture thickened, additional DMF (0.5 ml) was added. The reaction was then cooled, quenched with water, and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by flash column chromatography (Isco, 24 g column, 0 - 50% (3:1 EtOAc:EtOH) / heptane) to give the title compound (95 mg, 0.141 mmol, 77% yield). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.05 (s, 1H), 7.9 - 8.0 (m, 1H), 7.3 - 7.5 (m, 3H), 6.43 (d, 1H, J = 9.3 Hz), 5.7 - 5.9 (m, 2H), 4.9 - 5.6 (m, 2H), 2.3 - 2.4 (m, 3H), 2.24 (d, 3H, J = 2.0 Hz), 1.42 (s, 18H). MS (m / z) 561 (M + H - (t-butyl)).

[0193] Step C: (5-(3,4-Difluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate [Chemical formula]

[0194] A solution of di-tert-butyl phosphate ((5-(1-(3,4-difluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (88.8 mg, 0.132 mmol) dissolved in acetonitrile (660 μl) and water (660 μl) was added acetic acid (151 μl, 2.64 mmol), and the mixture was stirred at 70 °C for 1.5 h. The solvent was then concentrated, and the reaction product was purified by reverse-phase chromatography on an XSELECT CSH C18 column (150 mm × 30 mm inner diameter 5 μm packing diameter) at ambient temperature using 0.1% formic acid in acetonitrile in 0.1% formic acid in water as the eluent to give the title compound (46 mg, 0.081 mmol, 61% yield). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.05 (s, 1H), 7.9 - 8.0 (m, 1H), 7.3 - 7.5 (m, 3H), 6.41 (d, 1H, J = 9.8 Hz), 5.75 (br d, 2H, J = 4.4 Hz), 4.9 - 5.6 (m, 2H), 2.3 - 2.4 (m, 3H), 2.24 (d, 3H, J = 2.0 Hz), phosphate hydroxy proton exchange. MS (m / z) 559 (M - H - )。

[0195] Example 4: Dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl Step A: 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid

Chemical Structure

[0196] Under nitrogen, to 1-bromo-3,4-difluoro-2-methylbenzene (8.52 g, 41.1 mmol) in degassed anhydrous 1,4-dioxane (176 mL) were added 2-amino-4-chloro-5-fluorobenzoic acid (6 g, 31.7 mmol), cesium carbonate (25.8 g, 79 mmol), BINAP (1.971 g, 3.17 mmol), and Pd2(dba)3 (1.449 g, 1.583 mmol). The reaction mixture was stirred at 95 °C for 3 days. The brown suspension was cooled, diluted with ethyl acetate (350 mL), and filtered through celite. The filter cake was washed with EtOAc (3 × 200 mL). The filtrate was concentrated in vacuo at 40 °C to a dark oil, and a mixture of 1:1 DCM:heptane (150 mL) was added to give a precipitate. The solid was collected by vacuum filtration, washed with 10% DCM / heptane (3 × 25 mL), and air-dried under vacuum to give cesium 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoate (2.78 g, 5.58 mmol, 17.6% yield) as a tan-orange solid. The resulting celite filter cake containing additional product was transferred to a 1 L beaker, stirred with 200 mL of water at 25 °C, adjusted to pH 4 - 5 with 1N HCl, and DCM (500 mL) was added. The celite mixture was filtered, and the solid was retained for further isolation of the product. The layers of the filtrate were separated, the orange layer was dried over anhydrous sodium sulfate, filtered, and concentrated at 40 °C to an orange-yellow solid as the desired product to give 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid (0.5 g, 1.426 mmol, 4.5% yield) as an orange-yellow solid. The green celite filter cake solid from above was transferred to a 1 L beaker, MeOH (400 mL), MeCN (100 mL), and DCM (50 mL) were added, and the mixture was stirred at 25 °C for 1 h. The solid was collected by vacuum filtration and rinsed with MeOH (4 × 25 mL). The filtrate was concentrated at 40 °C to a brown solid as the further desired product to give 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid (7.65 g, 23.02 mmol, 72.7% yield). HPLC / MS 1.37 min (method a), [M+1] + 315.9。1 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 7.74 (d, J = 10.3 Hz, 1H), 7.19 (q, J = 9.3 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.91 (d, J = 6.4 Hz, 1H), 2.16 (d, J = 2.4 Hz, 3H).

[0197] Project B: 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide [Chemical Structure]

[0198] To a brown suspension of 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid (8.15 g, 25.8 mmol) in N,N-dimethylformamide (148 ml), 6-methoxy-2-methylpyridin-3-amine (4.46 g, 32.3 mmol) and HATU (11.78 g, 31.0 mmol) were added, followed by portionwise addition of DIEA (13.53 ml, 77 mmol) over 30 minutes to obtain a dark brown solution. This was stirred at 25 °C for 5 minutes and combined with another batch (2.70 g, 6.18 mmol of crude product) for workup and purification. To the crude reaction mixture, water (320 mL) was added portionwise with stirring, and the mixture was extracted with EtOAc (400 mL, then 100 mL). The combined organic layers were washed with water (2 × 200 mL), then brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo at 40 °C to obtain a brown oil. To this oil, 10 mL of DCM was added to form a granular solid, and 1:1 DCM:heptane (100 mL) was added and stirred for 3 hours to grind the solid. The solid was collected by vacuum filtration, and this cake was rinsed with 10% DCM / heptane (4 × 10 mL) and dried in vacuo overnight to obtain the title compound 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide (3.18 g, 6.93 mmol, 21.67% yield) as a tan solid. The filtrate was treated with 10 mL of DCM, then 1:1 DCM:heptane (100 mL) was added and stirred for 1 hour to grind the solid. The solid was collected by vacuum filtration, rinsed with heptane (4 × 10 mL), and air-dried under vacuum to obtain further product 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide (7.005 g, 15.27 mmol, 47.7% yield) as a brown solid. The resulting filtrate was purified on a 220 gram ISCO Gold silica column (Isco CombiFlash Rf, 0 - 25% EtOAc / heptane, 10 minute gradient, eluting at 125 mL / min).The pure fraction was concentrated at 40 °C to an orange solid and dried under high vacuum to give the title compound 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide (1.744 g, 3.80 mmol, yield 11.88%) as a bright orange solid. HPLC / MS 1.32 min (Method A), [M+H]. + 436.0。 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.27 (s, 1H), 7.96 (d, J = 10.3 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.28 (q, J = 9.3 Hz, 1H), 7.18 - 7.08 (m, 1H), 6.92 (d, J = 6.8 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 3H), 2.12 (d, J = 2.0 Hz, 3H).

[0199] Step C: 7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one

Chem.

[0200] To 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide (11.42 g, 26.2 mmol) in chloroform (262 mL) were added formaldehyde (1.967 g, 65.5 mmol) and sulfuric acid (3.49 mL, 65.5 mmol). The reaction mixture was stirred at 55 °C for 1 h to afford an orange gum at completion. Saturated sodium bicarbonate solution (25 mL) was added, the orange layer was separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organics were dried over anhydrous MgSO4 and concentrated in vacuo to a brown foam. This was combined with a separate batch of crude product (1.78 g, 3.99 mmol) for purification. The combined solid was dissolved in 20 mL of DCM and purified by Isco CombiFlash Rf (0% - 50% EtOAc in heptane; 330 g column, 25 min gradient). The pure fractions were collected and the product was isolated by concentration in vacuo to give 7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one (11.5 g, 25.7 mmol, 85% yield for both batches). HPLC / MS 1.31 min (Method B), [M+1] + 448.1. 1 H NMR (DMSO-d6, 400 MHz) δ 7.79 (d, 1H, J = 9.3 Hz), 7.59 (br d, 1H, J = 7.8 Hz), 7.3 - 7.5 (m, 1H), 7.16 (br d, 1H, J = 2.4 Hz), 6.71 (d, 1H, J = 9.3 Hz), 6.4 - 6.6 (m, 1H), 4.7 - 5.6 (m, 2H), 3.83 (s, 3H), 2.2 - 2.4 (m, 3H), 2.20 (d, 3H, J = 1.5 Hz).

[0201] Step D: 7-Chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-1-yl)-2,3-dihydroquinazolin-4(1H)-one

Chemical Structure

[0202] A solution of 7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one (11.43 g, 25.5 mmol) and HCl (128 ml, 638 mmol, 5N isopropanol solution) in isopropanol (255 ml) was heated to 90 °C for 1 hour under a condenser, 1,2-dichloroethane (85 ml) was added, and the solution was heated at 90 °C for 20 hours. The reaction mixture was cooled, and the solvent was removed in vacuo to give a white solid (9.9 g). This solid was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-1-yl)-2,3-dihydroquinazolin-4(1H)-one (8.55 g, 19.7 mmol, 77% yield) as a white solid. HPLC / MS 1.08 min (Method B), [M+1] + 434.1。 1 H NMR (DMSO-d6, 400 MHz) δ 11.75 (br s, 1H), 7.77 (d, 1H, J = 9.3 Hz), 7.35 (br dd, 2H, J = 10.3, 19.1 Hz), 7.13 (br s, 1H), 6.4 - 6.8 (m, 1H), 6.17 (br d, 1H, J = 9.3 Hz), 4.7 - 5.5 (m, 2H), 2.0 - 2.1 (s, 6H).

[0203] Step E: 7-Chloro-3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-2,3-dihydroquinazolin-4(1H)-one

Chemical formula

[0204] A solution of 7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one (1.784 g, 15.91 mmol) in ethyl acetate (96 ml) and N,N-dimethylformamide (DMF) (9.64 ml) was treated with chloromethyl chloroformate (3.77 ml, 42.4 mmol) and heated at 90 °C for 36 h and then at 25 °C for a total of 3 days. Further chloromethyl chloroformate (3.77 ml, 42.4 mmol) was added and the mixture was heated at 90 °C for 2 h. The reaction was cooled and 100 mL of water and 50 mL of brine were added. The product was extracted into 100 mL of EtOAc, the orange layer was separated, the aqueous layer was extracted with 75 mL of EtOAc, the combined organic layers were washed with brine (2×), saturated bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid (4.8 g). This solid was triturated with 10 mL of DCM to give a white solid (3 g). The filtrate was filtered to give a second crop. The solids were combined to give an off-white solid (3.69 g, 7.65 mmol, 72% yield). The remaining filtrate was concentrated in vacuo, the residue was dissolved in 1:1 hot EtOAc:MeOH and adsorbed onto silica. The residue was purified by Isco CombiFlash Rf (50% - 100% EtOAc in heptane; 40 g column, 20 min gradient). The pure fractions were pooled and concentrated in vacuo to give a further 500 mg (1.04 mmol, 9.8% yield) of the title compound as a white solid. HPLC / MS 1.25 min (Method B), [M+1] + 482.1。 1 H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, 1H, J = 9.3 Hz), 7.2 - 7.5 (m, 2H), 7.16 (br dd, 1H, J = 3.9, 8.3 Hz), 6.4 - 6.8 (m, 1H), 6.41 (d, 1H, J = 9.8 Hz), 5.5 - 6.3 (m, 2H), 4.7 - 5.4 (m, 2H), 2.2 - 2.5 (m, 3H), 2.20 (d, 3H, J = 2.0 Hz).

[0205] Project F: Di-tert-butyl phosphate ((5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl)

Chem.

[0206] To a solution of 7-chloro-3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-2,3-dihydroquinazolin-4(1H)-one (4.1 g, 8.50 mmol) and potassium di-tert-butyl phosphate (3.69 g, 14.88 mmol) in N,N-dimethylformamide (121 mL) was added tetrabutylammonium iodide (0.314 g, 0.850 mmol), and the mixture was heated at 70 °C for 1 h. The slightly gummy mixture was quenched with 40 mL of water and extracted with 40 mL of EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with water, saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow semi-solid. This solid was purified by Isco CombiFlash Rf (0 - 20% in DCM (3:1 EtOAc / EtOH), 80 g silica column, 20 min gradient). The pure fractions were pooled and concentrated in vacuo to give di-tert-butyl phosphate ((5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) as a solid. HPLC / MS 1.37 min (Method B), [M - 2 t Bu] + 544.0。 11H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, 1H, J = 9.3 Hz), 7.3 - 7.5 (m, 2H), 7.16 (br d, 1H, J = 1.0 Hz), 6.4 - 6.8 (m, 1H), 6.38 (d, 1H, J = 9.8 Hz), 5.7 - 5.9 (m, 2H), 4.7 - 5.5 (m, 2H), 2.2 - 2.4 (m, 3H), 2.1 - 2.2 (m, 3H), 1.3 - 1.5 (m, 18H).

[0207] Process G: Dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl

Chemical formula

[0208] Dibutyl phosphate ((5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (3.36 g, 5.12 mmol) was heated in acetone (26 ml) and water (26 ml) at 50 °C for 18 h. The reaction mixture was cooled to give a colorless solution, which was evaporated to dryness in vacuo at 40 °C to give a white foamy solid, which was dried under high vacuum to give dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (2.6 g, 4.78 mmol, 93% yield). HPLC / MS 0.73 min (method B), [M+H] + 544.0. 11H NMR (DMSO-d6, 400 MHz) δ 11.0 - 12.2 (m, 2H), 7.78 (d, 1H, J = 9.3 Hz), 7.38 (br d, 2H, J = 9.8 Hz), 7.1 - 7.2 (m, 1H), 6.5 - 6.8 (m, 1H), 6.37 (d, 1H, J = 9.8 Hz), 5.6 - 5.8 (m, 2H), 4.6 - 5.5 (m, 2H), 2.2 - 2.4 (m, 3H), 2.20 (d, 3H, J = 2.4 Hz).

[0209] Example 5: Methyl (5-(7-chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl) dihydrogen phosphate Step A: 7-Chloro-3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one

Chemical Structure

[0210] Under nitrogen, to a solution of 7-chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one (5.06 g, 12.17 mmol) and DABCO (0.683 g, 6.08 mmol) in ethyl acetate (111 ml) and N,N-dimethylformamide (DMF) (11.06 l), chloromethyl chloroformate (2.164 ml, 24.34 mmol) was added dropwise from a dropping funnel and the mixture was heated at 75 °C for 19 h. The reaction mixture was cooled, quenched with water and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (Isco, 300 g column, 0 - 50% (3:1 EtOAc:EtOH) / heptane) to give the title compound (3.88 g, 8.19 mmol, 67% yield). 11H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, 1H, J = 9.3 Hz), 7.47 (d, 1H, J = 9.8 Hz), 7.3 - 7.4 (m, 2H), 7.1 - 7.2 (m, 1H), 6.42 (d, 1H, J = 9.8 Hz), 6.3 - 6.4 (m, 1H), 5.5 - 6.2 (m, 2H), 4.7 - 5.5 (m, 2H), 2.3 - 2.5 (m, 3H), 2.26 (s, 3H), MS (m / z) 464 (M + H) + 。

[0211] Process B: Di-tert-butyl phosphate ((5-(7-chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl)

Chemical formula

[0212] To a solution of 7-chloro-3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-fluoro-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one (3.52 g, 7.58 mmol) and potassium di-tert-butyl phosphate (2.82 g, 11.37 mmol) in N,N-dimethylformamide (DMF) (100 ml) was added tetrabutylammonium iodide (0.280 g, 0.758 mmol), and the mixture was heated at 70 °C for 2.5 h. The reaction was cooled, quenched with water, and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by flash column chromatography (Isco, 300 g column, 0 - 20% (3:1 EtOAc:EtOH) / DCM) to give the title compound (3.52 g, 5.35 mmol, 70% yield). 11H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, 1H, J = 8.8 Hz), 7.45 (d, 1H, J = 9.8 Hz), 7.3 - 7.4 (m, 2H), 7.16 (br s, 1H), 6.3 - 6.6 (m, 2H, J = 9.8 Hz), 5.7 - 5.9 (m, 2H), 4.6 - 5.5 (m, 2H), 2.3 - 2.4 (m, 3H), 2.26 (s, 3H), 1.41 (d, 18H, J = 2.4 Hz), MS (m / z) 638 (M + H) + 。

[0213] Step C: Di-tert-butyl phosphate ((5-(7-chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl)

Chemical formula

[0214] A solution of di-tert-butyl phosphate ((5-(7-chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (3.47 g, 5.44 mmol) dissolved in acetone (40 ml) and water (30 ml) was heated at 50 °C for 16 h and stirred at room temperature for 6 h. The solvent was concentrated and then the title compound (2.74 g, 5.16 mmol, 95% yield) was obtained using a pump under high vacuum. 1 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, 1H, J = 9.3 Hz), 7.44 (d, 1H, J = 9.8 Hz), 7.3 - 7.4 (m, 2H), 7.18 (br d, 1H, J = 6.8 Hz), 6.3 - 6.5 (m, 2H, J = 9.8 Hz), 5.7 - 5.8 (m, 2H), 4.6 - 5.6 (m, 2H), 2.8 - 4.3 (m, 2H), 2.3 - 2.4 (m, 3H), 2.26 (s, 3H), MS (m / z) 526 (M + H) + 。

[0215]

Table 2

[0216]

Table 3

[0217] Example 6: Preparation of the crystalline form of dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl

[0218] The crystalline form of dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (Compound Example No. 4) was prepared and characterized by X-ray powder diffraction (XRPD) using a Cu radiation source.

[0219] Route 1 A solution of dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (35 mg, 0.064 mmol) was dissolved in ethyl acetate (161 μl) by heating until dissolved, then 10 drops of TBME were added and the solution was left at 25 °C for 4 hours. A white solid formed and the solvent was removed by evaporation to give dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl as a white solid (20.0 mg, 0.037 mmol, 57.1% yield), which showed some crystalline properties by XRPD (Figure 1).

[0220] Route 2 A solution of dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (875 mg, 1.61 mmol) in ethyl acetate (400 μl) was prepared by heating to 65 °C, then t-butyl methyl ether (10 drops, 401 μl) was added and the mixture was left to cool slowly to 25 °C over 4 days. The resulting solid was filtered, air-dried for 18 hours and then dried in a high vacuum dryer at 60 °C for 18 hours. The XPRD pattern (Figure 2) showed the crystalline properties of the desired product dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (0.500 g, 0.919 mmol, 57.1% yield). HPLC / MS 0.74 min (Method B), [M+H] + 544.0。 1HNMR (DMSO-d6, 400 MHz) δ 11.0 - 12.2 (m, 2H), 7.78 (d, 1H, J = 9.3 Hz), 7.38 (br d, 2H, J = 9.8 Hz), 7.1 - 7.2 (m, 1H), 6.5 - 6.8 (m, 1H), 6.37 (d, 1H, J = 9.8 Hz), 5.6 - 5.8 (m, 2H), 4.6 - 5.5 (m, 2H), 2.2 - 2.4 (m, 3H), 2.20 (d, 3H, J = 2.4 Hz).

[0221] Seed Preparation Di-tert-butyl phosphate ((5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (8.5 g, 12.957 mmol, 1 eq) was charged with acetonitrile (59.5 mL, 0.218 M, 7 volume eq) and water (8.5 mL, 1.524 M, 1 volume eq). The mixture was warmed to Tr = 50 °C (Tj = 53 °C - 54 °C) and stirred until a solution was obtained. Then, acetonitrile (34 mL, 0.381 M, 4 volume eq) was added while maintaining the mixture temperature in the range of 45 °C - 50 °C. Then, the mixture was cooled to 15 °C at a rate of 0.4 °C / min and stirred overnight. Then, the mixture was further cooled to 0 °C at a rate of 0.3 °C / min and stirred for 2 h. The resulting suspension was filtered and washed with acetonitrile (2 × 3 volumes). Then, the wet cake was dried in vacuo at room temperature to give 5.95 g of a dry crystalline solid, which was characterized by XRDP (Figure 5). The resulting crystalline solid was used as a seed in the following procedures (Route 3 and Route 4).

[0222] Route 3 Dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl was mixed with 7.4 volume equivalents of acetone and 2.6 volume equivalents of DMSO at 25 °C. Then, 0.3 volume equivalents of DMSO was added and the mixture was stirred until complete dissolution was achieved. Then, clarification filtration was performed. The following charges were with respect to the dissolved compound. 3 volume equivalents of water was added to the clear solution, and then 1.9 wt% of the crystalline compound was added as a seed. Then, the mixture was mixed for approximately 15 hours. A further 3 volume equivalents of water was added, and then 1.2 wt% of the crystalline compound was added as a seed. Then, the mixture was mixed for 40 minutes, and then 8.26 volume equivalents of water was added over 6 hours. Then, the mixture was aged for 19 hours to obtain a white suspension. Then, the suspension was vacuum filtered and the cake was washed continuously with 3 × 3 volume equivalents of water / acetone 2:1 (volume:volume) as a displacement wash. Then, the wet cake was dried at approximately 50 °C with slight aeration until a constant weight was achieved to obtain crystalline dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl (Figure 3).

[0223] Route 4 Dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl was mixed with 2.5 volume equivalents of acetone and 2.5 volume equivalents of DMSO at 25 °C until complete dissolution was achieved. Then, 5 volume equivalents of water were added, followed by the addition of the crystalline compound as 16 wt% seeds as a suspension in acetone / DMSO / water 1:1:2 (volume:volume:volume) relative to the seed mass. The mixture was then mixed for 18 h to obtain a white suspension. The suspension was then vacuum filtered and the cake was washed continuously with 3 × 3 volume equivalents of acetone as replacement washing. The wet cake was then dried at about 50 °C until a constant weight was obtained to give crystalline dihydrogen phosphate (5-(7-chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl. The XRPD pattern is shown in Figure 4 and the characteristic peaks, or diffraction angles (2θ) of the XRPD pattern, are listed in Table 2. XRPD was obtained using a Rigaku Miniflex X-ray diffractometer equipped with a Cu source using the following measurement parameters. Start position (°2θ) 5.0000 End position (°2θ) 40.0000 Step size 0.0200 Scan step time (seconds) 0.3478 Anode material Cu K-α1 [Å] 1.54060 K-α2 [Å] 1.54443 Generator settings 15 mA, 40 kV

[0224]

Table 4

[0225] Biological Assay Biological Assay 1: Na v 1.8 Inhibitory Activity Human Na v 1.8, Human Na v β1 and human TREK1 (HEK293-Na v 1.8)-expressing human embryonic kidney 293 cells (HEK293) were grown in a T150 cell culture flask in a 37 °C, 5% CO2 incubator. When the confluence reached 80 - 90% in the T150 cell culture flask, HEK293-Na v 1.8 was passaged every 2 - 3 days.

[0226] The pharmacological assessment of the compounds of the present invention was performed using a QPatch 48 HTX electrophysiology platform. HEK293-Na v 1.8 cells were prepared on the day of use by removing the culture medium, washing in DPBS, adding trypsin (2 mL to cover the surface, then aspirating 1 mL at 37 °C for 1 - 2 minutes), and then adding CHO-SFM II to obtain a suspension of 3 × 10 6 cells / mL.

[0227] The compounds of the present invention were prepared in an extracellular solution of the following composition: NaCl (145 mM), KCl (4 mM), CaCl2 (2 mM), MgCl (2 mM), HEPES (1 mM), glucose (10 mM), pH 7.4 using a NaOH osmolarity of 300 mOsM / L. The following intracellular solution composition was used: CsF (115 mM), CsCl (20 mM), NaCl (5 mM), EGTA (10 mM), HEPES (10 mM), sucrose (20 mM), pH 7.2 using a CsOH osmolarity of 310 mOsm / L.

[0228] Using the voltage-clamp mode in the QPatch 48 HTX system, a semi-inactivation state voltage protocol (V 1 / 2 ) was used to determine the pharmacological activity of the compounds of the present invention on the Na v 1.8 ion channel. V 1 / 2The protocol was utilized in the following voltage steps: An holding voltage of -100 mV was established, then a 20 ms (millisecond) voltage step to 0 mV (P1), then an inactivation voltage step at -46 mV for 8 seconds, then a step to -100 mV for 20 ms, then a 20 ms step to 0 mV, and then back to the holding voltage of -100 mV. This voltage protocol was repeated at a frequency of every 15 seconds, and the magnitude of the current was quantified at the P2 step throughout the recording. The inhibition of the measured current amplitude using the compound of the present invention was analyzed by fitting a 4 - 6 point dose - response curve to determine the 50% inhibitory concentration (IC 50 ). The P2 current was normalized according to the measurements taken at the baseline (media only) after fitting the compound (Input, at each test concentration) and the anode reference compound (FullResponse, to obtain complete blockade) to the following equation:

[0229]

Number

[0230] To evaluate the current rundown during the experiment, wells with media only were used to determine the normalized current of media only (n.I VEH ). To correct for the compound response to rundown, the current was corrected according to the following equation:

Number

[0231] Compound inhibition was fitted to the following Hill equation to estimate the 50% inhibitory concentration (IC 50 ):

Number

[0232] Y is equivalent to the media control (n.I RD_補正 ), C is the test concentration, IC 50It is the concentration of the test compound that inhibits the sodium current by 50%, and the normalized Rundown-corrected inhibition with respect to the h Hill coefficient.

[0233] The exemplary compounds shown in Tables 1 and 1A herein are active against the Nav1.8 sodium channel measured using the assays described herein and shown in Table 3 below.

[0234] Each of the compound examples listed in the present invention identified in the following chart was tested individually in at least one of the exemplified salt or free base forms. Unless otherwise specified, the test compound examples of the present invention are pharmacologically active Na v 1.8 pIC 50 (Qpatch)>5.0 was shown. In another aspect, the test compound examples of the present invention are pharmacologically active Na v 1.8 pIC 50 (Qpatch)>6.0 was shown.

[0235]

Table 5

[0236] Biological Assay 2: CAD Solubility The kinetic solubility was measured using a charged aerosol detector (CAD). The aqueous kinetic solubility at pH 7.4 was determined by measuring the concentration of the solute in the solution after precipitation from the DMSO stock solution. The DMSO stock solution was diluted 20-fold with phosphate buffered saline (PBS) pH 7.4, and the solubility of the compound was equilibrated at room temperature for 1 hour and then measured by HPLC-CAD. Calibration standards for ketoconazole and primidone were prepared by DMSO serial dilution at concentrations in the range of 0.016 - 4.5 mg / ml to obtain a calibration curve used to determine the solubility of the compounds as previously described in Max W. Robinson et al, Use of Calculated Physicochemical Properties to Enhance Quantitative Response When Using Charged Aerosol Detection, Anal. Chem., 2017, 89 (3), pp 1772-1777 (incorporated herein by reference). The CAD solubility of the prodrug compounds and the corresponding parent compounds of the present invention was measured as described above, and the results are shown in Table 4 below.

[0237]

Table 6

[0238] Biological Assay 3: Rat IV / PO Test An in vivo rat pharmacokinetic study was conducted to determine whether the prodrugs of the present invention are converted to their respective parent compounds upon administration. The rat pharmacokinetic study was performed in a crossover design over 2 test days including a 1-day recovery period between each test day. Three male Han Wistar rats with dual catheter insertions (femoral vein and carotid artery) were used for the study. A gastric catheter was also implanted in each rat for oral administration. The rats were administered by intravenous (IV) injection (femoral vein cannula) at 1 mg / kg for 60 minutes, and then subsequently orally at 2 mg / kg via the gastric cannula over 48 hours during the dosing period. The dosing solutions of the compound of Example 4 were prepared in 20% Cavitron / 5% DMSO / 75% water (intravenous) and 6% Cavitron / 5% DMSO / 89% water (oral) without pH adjustment. The dosing solutions were filtered using a 0.22 μm filter. The pH of the final dosing solution was 6.0.

[0239] During the intravenous study leg, blood samples were collected from the carotid artery catheter at the target times of 15, 30, 60 (end of infusion), 65, 75, 90, 120, 240, 360, 480, 720, and 1440 minutes after the start of the intravenous infusion of the compound of Example 4. During the oral study leg, blood samples were collected before dosing and at the target times of 15, 30, 60, 90, 120, 180, 240, 360, 480, 720, and 1440 minutes after oral administration. Blood samples (100 μL) were mixed with 100 μL of phosphatase inhibitor, and an aliquot of 50 μL of the mixture of blood and inhibitor was transferred to a non-heparinized tube and stored at approximately -80 °C until analysis. The concentration of the filtered dosing solution was first confirmed by diluting it stepwise in 50% aqueous acetonitrile using 0.1% formic acid, and then preparing a dilution solution (inhibitor for obtaining the determined actual concentration) in heparinized male Wistar Han blood. Three 50 μL aliquots were taken out, frozen, and stored at approximately 80 °C until analysis by the following LC-MS / MS. LC-MS / MS was used to quantify the compound of Example 4 and the corresponding parent compound of Example 4A in the biological samples obtained in the above in vivo study.

[0240] The samples were subjected to protein precipitation and then LC-MS / MS analysis using positive mode ionization against a set of calibration standards for the compounds prepared in the same matrix. Pharmacokinetic parameters for the test were derived from the concentration profiles against time. AUC 0~∞ (area under the extrapolated plasma concentration-time curve), AUC 0~t (area under the plasma concentration-time curve up to the final time point at which the drug was quantifiable), Cmax (maximum concentration), Tmax (time to reach Cmax), CL (total blood clearance), Vdss (volume of distribution at steady state), MRT (mean residence time), and t 1 / 2 (half-life) and other important pharmacokinetic parameters were determined for the compound of Example 4. AUC 0~∞ 、AUC 0~t 、Cmax, Tmax, MRT, and t 1 / 2 (half-life) and other important pharmacokinetic parameters were determined for the parent compound Example 4A. Descriptive statistical data of the pharmacokinetic parameters including mean values and standard deviations (SD) were calculated using Microsoft Excel. The data are shown in Tables 5A and 5B below. The data are reported as mean ± SD (N = 3).

[0241]

Table 7

[0242]

Table 8

[0243] Biological Assay 4: Manual Patch Clamp Electrophysiology Assay The pharmacological activities of the compounds of Example 4A and Example 5A (the active parent compounds of Prodrug Examples 4 and 5, respectively) were investigated by patch-clamp electrophysiological methods using a cell line in which human Nav1.8 was overexpressed in HEK293 cells. Using this technique, Nav1.8 can be activated by modulating the plasma membrane voltage, and then the channel function (Na+ conductance) can be directly quantified. The ability of Nav1.8 inhibitors to block the channel function in this system is a measure of target binding and inhibition.

[0244] Method Cell preparation: HEK293 cells (BIOCAT124824) overexpressing human Nav1.8 were grown in medium (DMEM / F12 containing 10% FBS, 2 mM GlutaMAX, 0.1 mM NEAA and 400 mg / ml G418, 100 mg / ml hygromycin-B and 0.625 mg / ml puromycin) at 37 °C and 5% CO2. When the confluence reached approximately 80%, the cells were passaged every 2 - 3 days. Preparation of electrophysiological recording solutions: Extracellular and intracellular solutions were prepared and used for voltage-clamp recordings in the following whole-cell patch-clamp experiments: Extracellular solution for voltage-clamp recordings: NaCl (145 mM), KCl (5.4 mM), CaCl2 (2 mM), MgCl2 (1 mM), HEPES (10 mM), glucose (5 mM); the pH was adjusted to 7.4 using NaOH and the osmotic pressure was adjusted to 310 mosM. Intracellular solution for voltage-clamp recordings: Cs methanesulfonate (85 mM), CsF (35 mM), CsCl (20 mM), NaCl (5 mM), EGTA (5 mM), HEPES (10 mM); the pH was adjusted to 7.3 using CsOH and the osmotic pressure was adjusted to 295 mosM.

[0245] Whole blood patch clamp test protocol: Whole-cell recordings were performed at room temperature (22 - 25 °C) using a MultiClamp 700B amplifier connected to a Digidata 1550A interface controlled by Clampex 10.6 software (Molecular Devices). The data acquisition rate was 20 kHz, and the signal was filtered at 5 kHz. Patch electrodes were pulled using a P-1000 Flaming / Brown micropipette puller (Sutter Instruments, Novato, CA, USA). The recording electrodes had a resistance of 1 - 1.5 MΩ when filled with internal solution, and the access resistance was generally <3 MΩ after the formation of the whole-cell configuration. Voltage error was minimized with 80 - 90% series resistance compensation. Cells were continuously perfused with extracellular solution by gravity at a rate of 0.5 ml / min, and solution aspiration was performed by a pump at a rate of 35 rpm to maintain a stable liquid level (Watson-Marlow 120U / DM2 peristaltic tube pump, Marlow, UK). A manual control first-step perfusion system (SF-77B, Warner Instruments) was used for drug delivery.

[0246] For each recording, 0.1% DMSO was perfused for 2 minutes to monitor the baseline, and the compound was applied for 6 minutes to ensure that inhibition reached a steady state.

[0247] Voltage clamp recording protocol: The compound effect was tested using a single-pulse rest protocol in which the cell was depolarized from a holding voltage of -120 mV to 0 mV for 50 ms. The peak current amplitude was measured from the activation current at 0 mV. Stimuli were applied every 20 seconds.

[0248] Test compounds: Compounds were dissolved in DMSO at a maximum concentration of 10 mM. For dose-response testing, stock solutions with concentrations in the range of 0.1 mM - 10 mM were prepared in DMSO. All different working concentrations were prepared in extracellular solution by 1:1000 dilution from each stock solution. For the vehicle group, 0.1% DMSO in extracellular solution was used as a negative control.

[0249] Measurement and normalization of Nav1.8 current amplitude: The Nav1.8 peak current induced by a test pulse of 0 mV was measured and analyzed by Clampfit 10.6 software (Molecular Devices, USA). In each recording, the total peak current amplitudes (I) obtained at different time points were normalized to the first data point at time 0 (I0) to obtain the I / I0 value.

[0250] Compound inhibition analysis: The compound inhibition effect was calculated using the following formula: % Inhibition = ([I / I0] ctrl - [I / I0] cmpd ) / [I / I0] ctrl × 100 [I / I0] ctrl is the average I / I0 of the last 3 sweeps in the baseline while applying 0.1% DMSO; [I / I0] cmpd is the average I / I0 of the last 3 sweeps during compound application when the inhibition reached a steady state.

[0251] Statistics and data visualization in GraphPad Prism: To create graphs from individual recordings, the normalized data and calculated inhibition rates were pasted into Prism 8.0 or 9.0 (Graphpad Software, San Diego, CA, USA). Fitting of the dose - response curve was performed in Prism using the four - parameter Hill’s equation: E = (E max - E min ) / [1 + (IC 50 / C)h] + E min , where E is the response, E max and E min are the maximum and minimum responses, respectively, there is no constraint on E max , and E min is constrained to 0. IC 50 is the concentration corresponding to a 50% inhibition effect, C is the drug concentration, and h is the Hill coefficient or Hill slope.

[0252] Result The potency of Compound Example 4A was tested in four separate experiments with three different synthetic batches, and the potency of Compound Example 5A was tested in one experiment. The measured IC 50 (concentration at which 50% inhibition of Nav1.8 was observed) for each compound is reported in Table 6 below. The results demonstrate that the compound of Example 4A is a more potent Nav1.8 inhibitor than the compound of Example 5A.

[0253] [Table 9]

Claims

1. The following: 【Chemical 1】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

2. The following: [Chemical Formula 2] (In the formula: R １ is -P(O)(OH)O － M ＋ , -PO(O−) ２ ·2M ＋ , or -PO(O−) ２ ·D ２＋ ; Each M ＋ is independently a pharmaceutically acceptable monovalent cation, and D ２＋ (wherein D is a pharmaceutically acceptable divalent cation) A pharmaceutically acceptable salt of a compound selected from the group consisting of, the compound according to claim 1.

3. The following: [Chemical Formula 3] The compound according to claim 1, which is, or a pharmaceutically acceptable salt thereof.

4. The following: 【Chemical Formula 4】 The compound according to claim 1, which is, or a pharmaceutically acceptable salt thereof.

5. The following: 【Chemical Formula 5】 The compound according to claim 1, which is, or a pharmaceutically acceptable salt thereof.

6. The following: 【Chemical Formula 6】 The compound according to claim 1, which is, or a pharmaceutically acceptable salt thereof.

7. The following: [Chemical Formula 7] The compound according to claim 1, which is, or a pharmaceutically acceptable salt thereof.

8. The following: [Chemical Formula 8] A compound selected from the group consisting of or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising the compound according to claim 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition according to claim 9 or claim 10, formulated for oral administration.

12. The pharmaceutical composition according to claim 9 or claim 10, formulated for intravenous administration.

13. A method for treating pain or pain-related diseases in a human in need of treatment, comprising administering to the human the compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12.

14. A method for treating atrial fibrillation in a human in need of treatment, comprising administering to the human the compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12.

15. The compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, for use in therapy.

16. The compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, for use in the treatment of pain or pain-related diseases.

17. The compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, for use in the treatment of atrial fibrillation.

18. Use of the compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, in the manufacture of a medicament for the treatment of pain or pain-related diseases.

19. Use of the compound according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, in the manufacture of a medicament for the treatment of atrial fibrillation.

20. The method according to claim 13, the compound for use according to claim 16, or the use according to claim 18, wherein the pain or pain-related disease is neuropathic pain, postoperative pain in the outpatient department, or osteoarthritis.

Images