Chemical compounds

Abstract

The present application provides compounds, pharmaceutical compositions and uses thereof for inhibiting Nav1.8 voltage-gated sodium channels and treating Nav1.8 mediated diseases, such as pain and pain-related diseases, cardiovascular diseases.

Description

Technical Field

[0001] The present invention relates to Na v 1.8 Inhibitor compounds or pharmaceutically acceptable salts or tautomeric forms thereof, corresponding pharmaceutical compositions or preparations, methods or processes for preparing compounds, methods, compounds, uses and / or combination therapies for treating pain and pain-related diseases and cardiovascular diseases. Background Art

[0002] Pain is a protective mechanism for animals to avoid potential tissue damage, however, there are many disease indications where pain exceeds its usefulness and becomes an ineffective burden. Indications where pain exceeds its usefulness can be broadly classified as those where nerve damage or injury is the cause (neuropathic pain), those where inflammatory responses or metabolic disorders sensitize the pain response (inflammatory pain), and those where injury or surgery results in a short-term elevation of the pain response (postoperative / spontaneous pain).

[0003] Voltage-gated sodium channels form the basis of electrical signal transduction in all excitable tissues by setting the threshold and potential for the rise of action potentials. There are nine different subtypes of voltage-gated sodium channels. v 1.1、Na v 1.7 Na v 1.8 and Na v Those with 1.9 are expressed primarily on peripheral nerves, where they control neuronal excitability. v 1.5 is the major sodium channel isoform expressed in cardiomyocytes. 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 v 1.6 is widely expressed in the central nervous system (CNS) and to some extent in the peripheral nervous system. The primary role of these nine voltage-gated sodium channels is similar, in that they control the influx of sodium into cells, but their biophysical properties differ, which greatly influences the physiological characteristics of their corresponding cell types (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are used clinically as antiarrhythmic and antiepileptic therapies, and these include lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these agents exhibit a lack of selectivity between different sodium channel subtypes, their therapeutic utility is greatly reduced due to adverse side effects mediated primarily by activity in the CNS and heart. This has stimulated efforts to develop novel drugs that are selective for specific sodium channel subtypes to avoid side effects in the CNS and cardiovascular system.

[0005] Na v The 1.8 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 the prominent physiological role of the channel in this tissue type and its restricted expression profile, it was proposed as a therapeutic target for analgesia when it was originally cloned from rat DRG (Akopian, 1996). Subsequently, Naβ was identified, cloned, and characterized from human DRG tissue. v 1.8 (Rabart 1998). v The closest related molecule of 1.8 is Na v 1.5, which share approximately 60% sequence homology. v 1.8 was previously known as SNS (sensory neuron sodium channel), PN3 (peripheral nerve sodium channel type 3), and because it exhibits characteristic pharmacological properties in terms of resistance to blockade by tetrodotoxin, it has also been described as a TTX-resistant sodium channel.

[0006] Na v Support for 1.8 as a therapeutic target for pain indications comes from several sources. v 1.8 has been shown to conduct the majority of the current during the rise of the action potential in DRG neurons (Blair & Bean, 2002) and is also critical to the repetitive firing ability of these neurons due to its re-firing rate (Blair and Bean, 2003). v Increased expression and function of Na1.8 is a response to painful stimuli such as inflammatory mediators (England 1996 & Gold 1996), nerve damage (Roza 2003 & Ruangsri 2011), and painful neuromas (Black 2008 & Coward 2000). Knockout of the gene encoding Nav1.8 in mice resulted in a reduced pain phenotype, particularly inflammatory challenges (Akopian 1999). v Knockdown of mRNA for Na 1.8 also resulted in a reduction in pain phenotypes in rodent models, particularly neuropathic models (Lai 2002). Pharmacological intervention via selective small molecule inhibitors has demonstrated efficacy in rodent models of inflammatory pain as well as neuropathic pain (Jarvis 2007 & Payne 2015). vSupportive genetic evidence for 1.8 also exists in patients with chronic neuropathic pain, where multiple gain of function mutations have been reported to be causative for paroxysmal painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). SUMMARY OF THE INVENTION

[0008] Therefore, it is necessary to develop new compounds, especially Na v 1.8 Inhibitor compounds having improved solubility and thus more conducive to alternative routes of administration, such as intravenous administration, for the treatment of pain and pain-related diseases and cardiovascular diseases. The present invention provides a compound having Na v 1.8 Inhibitory compounds and Na v 1.8 Prodrugs of compounds with inhibitory activity and the use of such compounds and prodrugs in the treatment of pain and pain-related diseases and cardiovascular diseases meet this need. The prodrugs of the present invention have improved solubility compared to their respective parent compounds and are therefore useful for intravenous (IV) administration and treatment of pain and pain-related diseases, where IV administration may be beneficial or preferred, such as in the treatment of acute pain.

[0009] In one aspect, a compound selected from the group consisting of:

[0010] or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, there is provided a compound selected from the group consisting of:

[0012] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, a pharmaceutical composition is provided, which comprises a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0014] In another aspect, provided is a method of treating pain or a pain-related disease in a human in need thereof, 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.

[0015] In another aspect, there is provided a method of treating atrial fibrillation in a human in need thereof, the method comprising administering to the human a compound of the invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.

[0016] In another aspect, there is provided a compound of the invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for use in therapy.

[0017] In another aspect, provided is 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 treating pain or pain-related diseases.

[0018] In another aspect, provided is 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 treating atrial fibrillation.

[0019] In another aspect, provided is use of the compound of the present invention or its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating pain or pain-related diseases.

[0020] In another aspect, provided is use of the compound of the present invention or its tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in preparing a medicament for treating atrial fibrillation. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline (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 prepared according to Scheme 1.

[0023] Figure 2 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline (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 prepared according to Scheme 2.

[0024] Figure 3 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline (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 prepared according to Scheme 3.

[0025] Figure 4 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline (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 prepared according to Scheme 4.

[0026] Figure 5 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline di-tert-butyl ((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) phosphate (seed material). DETAILED DESCRIPTION OF THE INVENTION

[0028] Various publications, articles and patents are cited or described in the background and throughout the specification. The discussion of documents, acts, materials, devices, articles and the like that have been included in this specification is for the purpose of providing context for the disclosure. Such discussion does not admit that any or all of these matters constitute part of the prior art related to the present disclosure.

[0029] 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 the invention belongs. Otherwise, certain terms used herein have the meanings defined in the specification.

[0030] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0031] The definitions of various groups and substituents of any formula disclosed herein, or a pharmaceutically acceptable salt thereof, provided throughout the specification are intended to specifically describe individually each compound species disclosed herein, as well as groups of one or more compound species.

[0032] The term "alkyl" refers to a straight or branched saturated hydrocarbon group having a specified number of carbon atoms. For example, the term "(C1-C6)alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and the term "(C1-C3)alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. In some embodiments, "Me" refers to methyl.

[0033] The terms "halogen" and "halo" represent chloro (-Cl), fluoro (-F), bromo (-Br), or iodo (-I) substituents.

[0034] When the term "alkyl" is used in combination with other substituents, such as "haloalkyl", the term "alkyl" is intended to encompass a divalent straight or branched chain hydrocarbon radical wherein the point of attachment is through the alkyl moiety.

[0035] The term "haloalkyl" refers to a group having one or more halogen atoms that may be the same or different on one or more carbon atoms of an alkyl portion having a specified number of carbon atoms, which is a straight or branched carbon group. For example, the term "halo (C1-C6) alkyl" refers to a group having one or more halogen atoms that may be the same or different on one or more carbon atoms of an alkyl portion having 1 to 6 carbon atoms, which is a straight or branched carbon group. 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.

[0036] Compound

[0037] In one aspect of the present invention, there is provided a compound selected from the group consisting of:

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Such compounds of the present invention are prodrugs of their respective parent compounds, which are Na v 1.8 Inhibitor compounds. The term "prodrug" refers to a compound that is a drug precursor that releases the parent compound in vivo through metabolic processes after administration and / or absorption. Generally, the biological activity of the prodrug is lower than that of the parent compound. The prodrug can also improve the physical properties and / or efficacy of the parent compound, such as reducing toxicity and reducing unwanted effects by better controlling the absorption, blood levels, metabolic distribution and / or cellular uptake of the parent compound. The prodrug may also have a higher solubility than the corresponding parent compound.

[0040] When the prodrug is administered to a subject (e.g., a human being), the prodrug moiety is cleaved to produce the parent compound. The terms "parent compound" and "parent drug" are used interchangeably herein and refer to a biologically active entity that is released by the enzymatic action of a metabolic or catabolic process or by a chemical process after the administration of the prodrug. The parent compound can also be the starting material for preparing the corresponding prodrug. Without wishing to be bound by any theory, the Na v 1.8 The inhibitory activity is mainly due to the cleavage of the prodrug to form the parent compound.

[0041] The prodrugs of the present invention generally have higher water solubility than the corresponding parent compound. This higher solubility is conducive to the use of higher doses of prodrugs, resulting in a greater drug load per unit dose. Therefore, the prodrug compounds of the present invention may be conducive to intravenous (IV) preparation and administration, and are therefore conducive to the treatment of pain and pain-related diseases, such as acute pain, where higher doses or administration by IV route may be beneficial.

[0042] In one embodiment, a compound is provided which is:

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, a compound is provided which is:

[0045] or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, a compound is provided which is:

[0047] or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, a compound is provided which is:

[0049] or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, a compound is provided which is:

[0051] or a pharmaceutically acceptable salt thereof.

[0052] In another aspect, there is provided a compound selected from the group consisting of:

[0053] Or its tautomer, or its pharmaceutically acceptable salt. Such compounds of the present invention are the parent compounds of certain prodrugs of the present invention, and have Na v 1.8 Inhibitory activity.

[0054] In one embodiment, a compound is provided which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, a compound is provided which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0056] Salt

[0057] It should be understood that the references to the compounds of the present invention and / or their corresponding tautomeric forms or their salts herein include the compounds and / or their corresponding tautomeric forms as free bases or acids, or as their salts, for example as their pharmaceutically acceptable salts. Therefore, in one embodiment, the present invention relates to the compounds of the present invention and / or their corresponding tautomeric forms. In another embodiment, the present invention relates to the salts of the compounds of the present invention and / or their corresponding tautomeric forms. In a further embodiment, the present invention relates to the pharmaceutically acceptable salts of the compounds of the present invention and / or their corresponding tautomeric forms. In another embodiment, the present invention relates to the compounds of the present invention and / or their corresponding tautomeric forms, or their salts. In another embodiment, the present invention relates to the compounds of the present invention and / or their corresponding tautomeric forms, or their pharmaceutically acceptable salts.

[0058] Due to their potential use in medicine, it will be appreciated that the salts of the compounds of the present invention and / or their corresponding tautomeric forms are preferably pharmaceutically acceptable.

[0059] The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation or other problems or complications, and with a reasonable benefit / risk ratio.

[0060] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound and exhibits minimal adverse toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In addition, the pharmaceutically acceptable salts of the compounds of the present invention and / or their corresponding tautomeric forms can be prepared during further processing of the free acid or base form, for example, in situ during manufacture into a pharmaceutical preparation.

[0061] Pharmaceutically acceptable salts include, but are not limited to, those listed in Berge, J. Pharm. Sci., 1977, 66, 1-19, or in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011.

[0062] Non-pharmaceutically acceptable salts are useful, for example, as intermediates in the preparation of the compounds of the present invention and / or their corresponding tautomeric forms or their pharmaceutically acceptable salts.

[0063] Suitable pharmaceutically acceptable salts may include acid or base addition salts. Such base addition salts may be formed by reacting a compound of the present invention and / or its corresponding tautomeric form (e.g., containing an acidic functional group) with an appropriate base, optionally in an appropriate solvent, such as an organic solvent, to produce a salt that can be separated by a variety of methods (including crystallization and filtration). Such acid addition salts may be formed by reacting a compound of the present invention and / or its corresponding tautomeric form (e.g., containing an alkaline amine or other alkaline functional group), optionally in an appropriate solvent, such as an organic solvent, to produce a salt that can be separated by a variety of methods (including crystallization and filtration).

[0064] Salts can be prepared in situ during the final separation and purification of the compound of the present invention and / or its corresponding tautomeric form. If the basic compound of the present invention and / or its corresponding tautomeric form are separated in the form of a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base. Similarly, if the compound of the present invention containing an acidic functional group and / or its corresponding tautomeric form are separated in the form of a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

[0065] It should be understood that if the compound of the present invention and / or its corresponding tautomeric form contains two or more basic moieties, the stoichiometry of the salt formation may include 1, 2 or more equivalents of acid. Such salts will contain 1, 2 or more acid counterions, for example dihydrochloride.

[0066] The scope of the present invention includes stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compounds of the present invention and / or their corresponding tautomeric forms, including substoichiometric salts, for example, wherein the counterion contains more than one acidic proton.

[0067] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (dextrorotatory camphorsulfonate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), Cinnamate, citrate, cyclaminate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (propionate lauryl sulfate), edetate (ethylenediaminetetraacetate), propionate lauryl sulfate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (ethanesulfonate), formate, fumarate, galactarate (mucates), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucoheptonate glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (naphthalene disulfonate), naphthalene-2-sulfonate (naphthalenesulfonate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (spicate), pantothenate, pectinate, persulfate, phenylacetate, phenethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (toluenesulfonate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophylline salt), thiocyanate, triethyl iodide, undecanoate, undecylenate, and valerate.

[0068] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, phenethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidol, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

[0069] In some embodiments, the compound is a pharmaceutically acceptable salt selected from:

[0070]

[0071] in:

[0072] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0073] Each M + are independently pharmaceutically acceptable monovalent cations; and

[0074] D 2+ It is a pharmaceutically acceptable divalent cation.

[0075] Monovalent cation (M + ) include but are not limited to alkali metal ions and ammonium ions. The term "alkali metal" as used herein refers to Group I elements, including but not limited to lithium (Li), sodium (Na), potassium (K), etc. + When each M + are independently monovalent cations, wherein each M + In some embodiments, when there are two M + When each M + same.

[0076] Divalent cations (D 2+ ) include but are not limited to alkaline earth metal ions and divalent aluminum ions. The term "alkaline earth metal" as used herein refers to Group II elements, including but not limited to calcium (Ca), magnesium (Mg), strontium (Sr), etc.

[0077] Other monovalent and divalent cations suitable for use in the present invention include monovalent or divalent ions of amino acid ions, such as monovalent or divalent ions of arginine, lysine, ornithine, etc. Monovalent and divalent cations including basic nitrogen-containing groups can be prepared by quaternization with reagents 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 dipentyl sulfate), etc.

[0078] In one embodiment, each M + In another embodiment, each M + Independently for Li + 、Na + or K + In another embodiment, each M + For Li + In another embodiment, each M + for Na + In another embodiment, each M + K + .

[0079] In one embodiment, each M + In another embodiment, each M + are independently of the formula -N(R a )4 ammonium ion, where each R a M is independently hydrogen, cyclohexyl or -(C1-C6)alkyl, which is optionally substituted with 1 to 6 -OH groups. + are independently selected from NH4 + , ethanolamine ion In another embodiment, each M + NH4 + In another embodiment, each M + for (ethanolamine ion).

[0080] In one embodiment, D 2+ is an alkaline earth metal ion. In another embodiment, D 2+ Mg 2+ , Ca 2+ or Sr 2+ In another embodiment, D 2+ Mg 2+ or Ca 2+ In another embodiment, D 2+ Mg2+ In another embodiment, D 2+ It is Ca 2+ .

[0081] In one embodiment, a compound is provided which is:

[0082] in:

[0083] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0084] Each M + are independently pharmaceutically acceptable monovalent cations; and

[0085] D 2+ It is a pharmaceutically acceptable divalent cation.

[0086] In one embodiment, a compound is provided which is: in:

[0087] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0088] Each M + are independently pharmaceutically acceptable monovalent cations; and

[0089] D 2+ It is a pharmaceutically acceptable divalent cation.

[0090] In one embodiment, a compound is provided which is: in:

[0091] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0092] Each M +are independently pharmaceutically acceptable monovalent cations; and

[0093] D 2+ It is a pharmaceutically acceptable divalent cation.

[0094] In one embodiment, a compound is provided which is:

[0095] in:

[0096] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0097] Each M + are independently pharmaceutically acceptable monovalent cations; and

[0098] D 2+ It is a pharmaceutically acceptable divalent cation.

[0099] In one embodiment, a compound is provided which is:

[0100] in:

[0101] R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ;

[0102] Each M + are independently pharmaceutically acceptable monovalent cations; and

[0103] D 2+ It is a pharmaceutically acceptable divalent cation.

[0104] Solvate / Crystal / Co-Crystal

[0105] It should be recognized that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize from solvents. These complexes are referred to as "solvates". For example, complexes with water are referred to as "hydrates". Solvents with high boiling points and / or solvents that are prone to hydrogen bonding (such as water, ethanol, isopropanol and N-methylpyrrolidone) can be used to form solvates. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. The compounds of the present invention and / or their corresponding tautomeric forms or salts thereof can exist in solvated and non-solvated forms.

[0106] The compounds of the invention may be in crystalline or amorphous form. The thermodynamically most stable crystalline forms of the compounds of the invention are of particular interest.

[0107] The crystalline forms of the compounds of the invention can be characterized and distinguished by a variety of 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).

[0108] 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.

[0109] In another 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 in that when Cu K α When measured by radiometric X-ray powder diffraction (XRPD) pattern, the X-ray powder diffraction (XRPD) pattern comprises diffraction angles of about 11.9, about 13.2, about 14.7, and / or about 16.0 degrees 2θ.

[0110] In another 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 in that when Cu K α When measured by radiation, the diffraction angles included in its X-ray powder diffraction (XRPD) pattern are basically as shown in Table 2.

[0111] 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 in that its X-ray powder diffraction (XRPD) pattern is substantially the same as Figure 4 Consistency

[0112] When it is stated herein that a peak is present in an XRPD pattern at a given value, it is generally meant that the peak is within ±0.2, e.g. ±0.1, of the quoted value.

[0113] Stereoisomers

[0114] The compounds of the present invention and / or their corresponding tautomeric forms and pharmaceutically acceptable salts thereof may contain one or more asymmetric centers (also referred to as chiral centers) and may therefore exist as individual enantiomers, diastereomers, or other stereoisomeric forms or mixtures thereof. Chiral centers (e.g., chiral carbon atoms) may also be present in substituents (e.g., alkyl groups). When the stereochemistry of a chiral center present in a compound of the present invention or any chemical structure shown herein is not specified, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Therefore, the compounds of the present invention and / or their corresponding tautomeric forms and pharmaceutically acceptable salts thereof containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.

[0115] The individual stereoisomers of the compounds of the invention containing one or more asymmetric centers and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof can be resolved by methods known to those skilled in the art. For example, such resolution can be performed as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific 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 with bound chiral ligands or in the presence of a chiral solvent. The skilled person will understand that in the case where the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, additional steps are required to liberate the desired form. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0116] isotope

[0117] The present invention also includes all suitable isotopic variations of the compounds described herein and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the present invention and / or its corresponding tautomeric forms or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F and 36 Certain isotopic variations of the compounds of the present invention and / or their corresponding tautomeric forms or their salts or solvates, for example, wherein a radioactive isotope such as 3 H or 14 C, can be used in drug and / or substrate tissue distribution studies. Tritiated isotopes, i.e. 3 H, and carbon-14 isotopes, i.e. 14 C is particularly preferred because of its ease of preparation and detectability. In addition, isotopes such as deuterium, i.e. 2 H substitution may provide certain therapeutic advantages due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopic variations of the compounds of the invention and / or their corresponding tautomeric forms or pharmaceutically salts thereof can generally be prepared by conventional procedures, for example by the illustrative methods or as described in the examples hereinafter, using appropriate isotopic variations of suitable reagents.

[0118] Tautomer

[0119] In addition, the compounds of the present invention can exist as tautomers or in tautomeric forms. It should be understood that any reference to a named compound or a structural description compound is intended to cover all tautomers of such a compound. It is generally understood in the chemical field that tautomers are structural or compositional isomers of compounds that are easily interconverted. This reaction usually results in the relocation of protons. Structural isomers or compositional isomers (according to IUPAC) are isomers in which molecules with the same molecular formula have different bonding patterns and atomic structures, in contrast to stereoisomers, in which the molecular bonds are always in the same order and only the spatial arrangement is different. The concept of tautomerism is called tautomerism. The chemical reaction in which the two are mutually converted is called tautomerization. Care should be taken not to confuse tautomers with the description of "contributing structures" in chemical resonance. Tautomers are different chemical substances that can be identified by their different spectral data, and resonance structures are only convenient descriptions and do not actually exist. For example, the 2-pyridone ring exhibits tautomerism, where the proton attached to the nitrogen can move to the oxygen, forming the tautomeric form 2-hydroxypyridine:

[0120]

[0121] Pharmaceutical composition

[0122] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention according to any embodiment disclosed herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (also referred to as a carrier and / or diluent in the pharmaceutical field). An excipient is acceptable in the sense that it is compatible with the other ingredients in the formulation and is harmless to its recipient (i.e., the patient).

[0123] Pharmaceutically acceptable excipients are non-toxic and should not interfere with the efficacy of the active ingredient. Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected, route of administration, etc. 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, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. 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).

[0124] The pharmaceutical composition may be suitable for administration by any appropriate or suitable route, such as by systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, etc. Parenteral administration is typically by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether by inhalation through the mouth or through the nasal passages. Typically, administration is by an oral route or a parenteral route, such as an intravenous route.

[0125] Pharmaceutical compositions suitable for oral administration can be presented as solid dosage forms such as tablets, capsules, caplets, lozenges, pills; powders; or liquid dosage forms such as solutions, suspensions, syrups, elixirs or emulsions, etc. Pharmaceutical compositions suitable for parenteral administration can be presented as solutions, suspensions and powders for reconstitution.

[0126] In some embodiments, the pharmaceutical compositions of the invention are formulated for oral administration. In other embodiments, the pharmaceutical compositions of the invention are formulated for intravenous administration.

[0127] In general, the pharmaceutical compositions of the present invention are prepared using conventional materials and techniques (eg, mixing, blending, etc.). Some methods commonly used in the art are described in Remington's PHARMACEUTICAL SCIENCES (Mack Publishing Company).

[0128] Solid oral dosage forms (e.g., tablets and capsules) can be prepared by mixing the compound of the present invention with excipients such as diluents and fillers (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), etc. Pharmaceutical compositions suitable for parenteral administration can be injections prepared by mixing powders, granules or tablets with carriers (e.g., distilled water, physiological saline, etc.), and the pH value can be adjusted with alkali, etc.

[0129] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of the present invention and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0130] The compounds and pharmaceutical compositions of the present invention as defined herein can be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals over a given period of time. For example, the dose can be administered one, two, three or four times a day. The dose can be administered until the desired therapeutic effect is achieved or administered indefinitely to maintain the desired therapeutic effect. The dose of the compound of the present invention can be in the range of 0.001 mg / kg to 100 mg / kg, for example 0.001 mg / kg to 50 mg / kg. Preferably, the dose selected is oral or parenteral.

[0131] According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition, comprising mixing (or blending) a compound of the present invention or a tautomer thereof or a salt thereof (eg, a pharmaceutically acceptable salt thereof) with at least one pharmaceutically acceptable excipient.

[0132] Synthetic schemes and general preparation methods

[0133] The present invention also relates to methods for preparing the compounds of the present invention disclosed herein. The compounds of the present invention can be prepared by a variety of methods using conventional organic synthesis methods described in the following schemes, more specifically illustrated by the exemplary compounds in the Examples section herein, or using the knowledge of a skilled organic chemist. Suitable synthetic routes are described in the following general reaction schemes. The synthetic procedures provided in the following schemes are suitable for producing the compounds of the present invention disclosed herein, which have various functional groups defined using appropriate precursors.

[0134] It will be appreciated by those skilled in the art that, when preparing the compounds of the present invention, it may be necessary and / or desirable to protect one or more sensitive groups in a molecule or a suitable intermediate to prevent undesirable side reactions. It will be appreciated by those skilled in the art that, in the preparation of the compounds of the present invention (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), it may be necessary and / or desirable to protect one or more sensitive groups in a molecule or a suitable intermediate to prevent undesirable side reactions. It will be appreciated by those skilled in the art that, if the substituents described herein are incompatible with the synthetic methods described herein, the substituents may be protected with suitable protecting groups that are stable to the reaction conditions. The protecting groups may be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups used according to the present invention are well known to those skilled in the art and may be used in a conventional manner. For example, see "Protective Groups in Organic Synthesis" by T.W.Green and PGM Wets (Wiley & Sons, 1991) or "Protecting Groups" by PJ Kocienski (Georg Thieme Verlag, 1994). If desired, subsequent deprotection yields compounds of generally disclosed properties. In some cases, a substituent may be specifically selected to be reactive under the reaction conditions used. In these cases, the reaction conditions convert the selected substituent into another substituent that can serve as an intermediate compound or the desired substituent in the target compound.

[0135] Although the schemes shown below represent methods for preparing the compounds of the present invention, they are intended only to illustrate methods that can be used to make the compounds of the present invention. Intermediates (compounds used to prepare the compounds of the present invention) can also exist in the form of salts. Therefore, when referring to intermediates, the phrase "compound of formula (number)" refers to a compound having the structural formula or a pharmaceutically acceptable salt thereof. The compound names are generated using the software naming program ChemDraw 5Ultra v16.0, which can be purchased from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts, 02451, USA.

[0136] The following schemes and examples illustrate several methods for preparing the compounds of the present invention. Starting materials are commercially available or prepared according to known methods in the literature or as illustrated.

[0137] General synthetic scheme

[0138] Scheme I

[0139]

[0140] The preparation of the compounds of the present invention generally begins with the synthesis of N-substituted-2-aminoaromatic derivatives I-3 (Scheme I). Arylation of the aniline nitrogen with an appropriate aryl halide can be carried out using a transition metal catalyst (e.g., Pd2(dba)3 or Cu / CuO), a suitable ligand (e.g., BINAP or Xantphos) and an inorganic base (e.g., Cs2CO3 or K2CO3) in a suitable solvent (e.g., 1,4-dioxane). In certain cases where X=F, the aryl group can be synthesized by S in the presence of a base (e.g., diisopropylethylamine (DIPEA)) in a suitable solvent (e.g., dimethylformamide (DMF)). N Ar reaction to achieve conversion

[0141] In each of intermediates I-1, I-2 and I-3 in Scheme I, R1 and R2 are each independently halogen (eg, -F or -Cl) or haloalkyl- (eg, -CF3); R3 (if present) is optionally substituted phenyl; and R is H or alkyl.

[0142] Solution II

[0143]

[0144] The intermediate N-substituted-2-aminoaromatic acid derivative I-3 prepared as shown in Scheme I can be converted to II-1 by coupling I-3 with a suitable aryl-NH2 (e.g., 2-methoxy-4-aminopyridine) under various amide coupling conditions known to those skilled in the art to give the corresponding amide II-1 (Scheme II). For example, a standard coupling agent such as EDC / HOBT, HATU, HBTU or T3P can be used in the presence of an amine base such as triethylamine or Hünig's base (diisopropylethylamine) in a suitable solvent (usually DMF, DMA or acetonitrile). Alternatively, the acid can be converted to the corresponding acid chloride using a reagent such as thionyl chloride or oxalyl chloride, and then the acid chloride is reacted with a suitable aryl-NH2 (e.g., 2-methoxy-4-aminopyridine) in the presence of an acid scavenger or base (e.g., pyridine, 2,6-lutidine, triethylamine or Hünig's base) in a suitable solvent (e.g., dichloromethane or pyridine) to give the desired coupling product II-1. The formation of the dihydroquinazolinone ring system (as shown in II-2) involves the reaction of II-1 with formaldehyde or a suitable equivalent. For example, the reaction can be achieved using formaldehyde (as gaseous formaldehyde, paraformaldehyde or s-trioxane) in the presence of an acid (preferably PTSA or sulfuric acid). Alternatively, the dihydroquinazolinone ring system can be formed by reacting with II-1 using diiodomethane or chloroiodomethane as a formaldehyde equivalent. In this cyclization reaction, a base (usually Cs2CO3 or NaH) can be used to react in a suitable solvent (usually acetonitrile or DMF). The choice of using formaldehyde or diiodomethane depends on the specific reactivity characteristics of the substrate II-1.

[0145] In each of intermediates I-3, II-1 and II-2 in Scheme II, R1 and R2 are each independently halogen (eg, -F or -Cl) or haloalkyl- (eg, -CF3); R3 is optionally substituted phenyl; and R4 and R5 are each independently hydrogen or -CH3.

[0146] Scheme III

[0147]

[0148] In a variation of the methods described in Schemes I and II, compounds can be prepared as shown in Scheme III. For activated 2-halo acids (III-1; X1 = Cl, Br or I), reaction with a suitable aniline or amine nucleophile can be carried out in the presence of a catalyst (e.g., Pd2(dba)3 or Cu / CuO), a suitable ligand (e.g., BINAP or Xantphos) and an inorganic base (typically Cs2CO3 or K2CO3), typically at elevated temperatures using standard heating or microwave irradiation, to afford III-2 in a suitable solvent (e.g., 1,4-dioxane, toluene or 2-ethoxyethanol). In some cases where X1 = F, reaction can be carried out by S in the presence of a base (e.g., DIPEA). N Ar reaction is carried out in a suitable solvent such as DMF to effect the transformation. III-2 can be converted to III-3 and finally to III-4 as described in Scheme II.

[0149] In each of the intermediates III-1, III-2, III-3 and III-4 in Scheme III, R1 and R2 are each independently halogen (e.g., -F or -Cl) or haloalkyl- (e.g., -CF3); R3 (if present) is optionally substituted phenyl; R4 and R5 are each independently hydrogen or -CH3; and X is CH or N.

[0150] Scheme IV

[0151]

[0152] As shown in Scheme IV, the conversion of compound III-4 to pyridone IV-1 can be achieved by reacting compound III-4 with a mixture of TMS-chloride and NaI or a TMS-iodide solution in a neutral solvent (such as acetonitrile) at high temperature. Compound IV-1 can react with chloromethyl ester in a suitable solvent (such as EtOAc and DMF) in the presence of an organic base (such as DABCO) to provide chloromethyl pyridone IV-2. Compound IV-2 reacts with di-tert-butyl potassium phosphate in the presence of a phase transfer catalyst (such as TBAI) in solvent DMF at high temperature to provide compound IV-3. Removal of the tert-butyl protecting group under acidic conditions (such as acetic acid in acetonitrile and water) provides a prodrug compound of the present invention.

[0153] In each of intermediates III-4, IV-1, IV-2, IV-3 and IV-4 in Scheme IV, R1 and R2 are each independently halogen (e.g., -F or -Cl) or haloalkyl- (e.g., -CF3); R3 is optionally substituted phenyl; R4 and R5 are each independently hydrogen or -CH3; and X is CH or N.

[0154] Method / Purpose

[0155] In general, the present invention also relates to the compounds and / or pharmaceutical compositions described herein for use as medicaments or in therapy.

[0156] The compounds of the invention as defined herein are voltage-gated sodium channels, in particular voltage-gated sodium channels Na v 1.8 inhibitor. v 1.8 Inhibitors The activity of a compound can be determined according to the methods generally described in the Examples herein or according to methods available to one of ordinary skill in the art.

[0157] In one aspect, the invention relates to compounds and pharmaceutical compositions as described herein as voltage-gated sodium channels (particularly Na v 1.8) Use of inhibitors.

[0158] In one embodiment, the invention relates to a method of inhibiting a voltage-gated sodium ion channel in a subject in need thereof, 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-gated sodium channel is Na v 1.8.

[0159] In one embodiment, the invention relates to a compound of the invention or a pharmaceutical composition of the invention for inhibiting a voltage-gated sodium ion channel. In another embodiment, the voltage-gated sodium channel is Na v 1.8.

[0160] In one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for inhibiting a voltage-gated sodium ion channel. In another embodiment, the voltage-gated sodium channel is Na v 1.8.

[0161] Without wishing to be bound by any particular theory, the compounds and compositions of the present invention are particularly useful for treating diseases related to Na v 1.8 Diseases, conditions or disorders related to activation or overactivity of Na vWhen activation or overactivity of 1.8 is associated with a specific disease, condition, or disorder, the disease, condition, or disorder may also be referred to as "Na v 1.8-mediated diseases, conditions or disorders". Exemplary Na v 1.8-mediated diseases, conditions and disorders include pain and pain-related diseases and cardiovascular diseases, such as atrial fibrillation.

[0162] According to an embodiment of the present invention, the pain-related disease is pain caused by any of a variety of diseases of different etiologies described throughout the present disclosure. In some embodiments, the pain or pain-related disease is neuropathic pain, chronic pain, acute pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, cancer pain, idiopathic pain, multiple sclerosis, Summer-Mar- Figure 3 Charcot-Marie-Tooth syndrome or incontinence.

[0163] In some embodiments, pain or pain-related diseases are neuropathic pain or chronic neuropathic pain. In some embodiments, pain or 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.

[0164] In some embodiments, the pain or pain-related disease is neuropathic pain selected from post-herpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic headache.

[0165] In some embodiments, the pain or pain-related disease is neuropathic pain or chronic neuropathic pain selected from diabetic peripheral neuropathy, pain caused by neuropathy, nervous system or neuronal damage, pain-related nerve damage, neuropathic pain and related acute or chronic pain, post-herpetic 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 injury 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.

[0166] In some embodiments, the pain or pain-related disorder is visceral pain, wherein the visceral pain is inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0167] In some embodiments, the pain or pain-related disorder is musculoskeletal pain, wherein the musculoskeletal pain is osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0168] In some embodiments, the pain or pain-related disorder is idiopathic pain, wherein the idiopathic pain is fibromyalgia.

[0169] In some embodiments, pain or pain-related diseases are chronic or acute preoperative related pain or chronic or acute postoperative related pain. Postoperative related pain includes non-hospitalized postoperative pain. Non-hospitalized surgery (also called outpatient surgery) refers to surgery on the same day that does not require an overnight stay in a hospital or other medical institution. In some embodiments, preoperative related pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, dental pain, or inflammatory pain. In some embodiments, postoperative related pain is selected from bunionectomy pain, hernia repair pain, breast surgery pain, or cosmetic surgery pain.

[0170] In some embodiments, pain or pain-related diseases are pain caused by trauma or iatrogenic medical or dental surgery. As used herein, the term "iatrogenic" refers to pain unintentionally induced by medical or dental personnel (such as surgeons or dentists) during medical or dental treatment or diagnostic procedures, including but not limited to pain caused by preoperative (i.e., "before"), perioperative (i.e., "during" or during non-surgical or surgical treatment) and postoperative (i.e., postoperative, postoperative or surgically induced) medical or dental surgery.

[0171] In some embodiments, the pain or pain-related disorder is nociceptive pain, wherein the nociceptive pain is postoperative pain, cancer pain, back and craniofacial pain, osteoarthritis pain, dental pain, or diabetic peripheral neuropathy.

[0172] In some embodiments, pain or pain-related diseases are inflammatory pain. Inflammatory pain can be pain of various physiological causes. In some embodiments, inflammatory pain is selected from pain associated with: osteoarthritis, rheumatoid arthritis, rheumatism, tenosynovitis and gout, tendinitis or bursitis of the shoulder, 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 arthritis pain and related neuropathic pain or acute pain. In some embodiments, inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis or juvenile arthritis. In some embodiments, the inflammatory pain is selected from rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, juvenile arthritis, rheumatism, 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 arthritic pain, and related neuropathic pain. In some embodiments, the inflammatory pain is rheumatoid arthritis pain or vulvar pain.

[0173] In some embodiments, the inflammatory pain is osteoarthritis, chronic osteoarthritis pain (eg, hip or knee), or chronic inflammatory demyelinating polyneuropathy.

[0174] In some embodiments, pain or pain-related diseases are musculoskeletal pain. In some embodiments, musculoskeletal pain is selected from bone and joint pain, osteoarthritis, low back pain and neck pain, or pain caused by physical trauma or amputation. In some embodiments, musculoskeletal pain is selected from bone and joint pain, osteoarthritis (e.g., knee, hip), tendinitis (e.g., shoulder), bursitis (e.g., shoulder) tenosynovitis, low back pain and neck pain, sprains, strains, or pain caused by physical trauma or amputation.

[0175] In some embodiments, the pain or pain-related disease is a pain disorder associated or related to nerve or neuronal damage caused by a disease selected from the group consisting of: neuropathy, pain-related nerve injury, pain-related root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal severe pain syndrome (PEPD), burning mouth syndrome; central pain syndrome caused by damage at the level of the nervous system, traumatic nerve injury, nerve compression or entrapment, congenital indolence (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, or vasculitic neuropathy.

[0176] In some embodiments, the pain or pain-related disorder is pain resulting from trauma, or pain resulting from iatrogenic, medical, or dental procedures.

[0177] In some embodiments, the pain or pain-related disorder is myofascial pain, myositis or muscle inflammation, repetitive motion pain, complex regional pain syndrome, sympathetically maintained pain, cancer, toxin and chemotherapy-related pain, postoperative pain syndrome and / or associated phantom limb pain, postoperative medical or dental surgery or treatment pain, or HIV-related pain or HIV treatment-induced pain.

[0178] In some embodiments, the pain or pain-related disease is neuropathic pain or other pain-related diseases are selected from peripheral neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuralgia (SFN), paroxysmal excruciating pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, multiple sclerosis pain, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, vulvodynia, pain caused by physical trauma, pain after amputation, neuroma pain, phantom limb pain, cancer, toxins or chronic inflammatory conditions.

[0179] In some embodiments, the pain or pain-related disorder is acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epilepsy, neurodegenerative disease, psychiatric disorder, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, 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 disorders.

[0180] In some embodiments, the pain or pain-related disease is 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, Xia-Ma- Figure 3 Neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury / motion pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory, burn and trauma pain, acute intermittent pain , endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, maxillofacial pain including sinusitis pain, dental pain, multiple sclerosis (MS) pain, depressive pain, leprosy pain, Behcet's disease pain, adiposity dolorosa, phlebitis pain, Guillain-Barré pain, leg pain and mobile toe syndrome, Haglaud syndrome, erythromelalgia pain, Fabry's disease pain, bladder and genitourinary disorders including urinary incontinence, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) (type I and II), widespread pain, paroxysmal excruciating pain, pruritus, tinnitus or angina-induced pain.

[0181] In another aspect, the invention relates to the use of the compounds and pharmaceutical compositions of the invention in methods and medicaments for the treatment of cardiovascular diseases, disorders and conditions, including atrial fibrillation and cardiac arrhythmias.

[0182] In some embodiments, the cardiovascular disease is atrial fibrillation that is idiopathic in nature or caused by a disease as defined herein. Atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic renal disease. In specific embodiments, atrial fibrillation is selected from paroxysmal, persistent, or chronic atrial fibrillation.

[0183] In some embodiments, the cardiovascular disease comprises arrhythmia.

[0184] Therefore, in another aspect, the present invention also provides a method of treating 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 cardiovascular disease.

[0185] The term "treat" refers to alleviating a particular disorder, eliminating or alleviating one or more symptoms of a disorder, slowing or eliminating the progression of a disorder, and delaying the recurrence of a disorder in a patient or subject previously suffering from the disorder.

[0186] 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 tautomer or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in the human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0187] The term "subject" refers to a human body.

[0188] In one aspect, the invention relates to a method of treating pain or a pain-related disorder as defined herein in a human in need thereof, comprising administering to said human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0189] In one embodiment, there is provided a method of treating acute pain or chronic pain in a human in need thereof, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention.

[0190] In one embodiment, a method of treating pain caused by trauma, pain caused by iatrogenic medical or dental surgery, or pre- or post-operative related pain in a human in need thereof is provided, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention.

[0191] In one embodiment, there is provided a method of treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain in a human in need thereof, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention.

[0192] In one embodiment, a method of treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy in a human in need thereof is provided, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention.

[0193] In one embodiment, there is provided a method of treating inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, and chronic inflammatory demyelinating polyneuropathy in a human in need thereof, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention.

[0194] In one embodiment, there is provided a method for treating pain or a pain-related disease in a person in need thereof, the pain or pain-related disease being selected from neuropathic pain, non-hospitalized postoperative pain, and osteoarthritis, comprising administering to the person a compound of the present invention as described herein or a pharmaceutical composition of the present invention. In some embodiments, pain or a pain-related disease is neuropathic pain. In some embodiments, pain or a pain-related disease is chronic neuropathic pain. In some embodiments, pain or a pain-related disease is small fiber neuropathy. In some embodiments, pain or a pain-related disease is non-hospitalized postoperative pain. In some embodiments, pain or a pain-related disease is osteoarthritis. In some embodiments, pain or a pain-related disease is knee osteoarthritis and / or hip osteoarthritis.

[0195] In another aspect, the present 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 a pain-related disease as defined herein.

[0196] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of acute pain or chronic pain.

[0197] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of pain resulting from trauma, pain resulting from iatrogenic medical or dental procedures, or pain associated with pre- or post-surgery.

[0198] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain or idiopathic pain.

[0199] In one embodiment, a compound of the invention or a pharmaceutical composition of the invention is provided for use in the treatment of neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy.

[0200] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain and chronic inflammatory demyelinating polyneuropathy.

[0201] In one embodiment, a compound of the invention or a pharmaceutical composition of the invention is provided for the treatment of pain or pain-related diseases selected from neuropathic pain, non-hospitalized postoperative pain, and osteoarthritis. In some embodiments, pain or pain-related diseases are neuropathic pain. In some embodiments, pain or pain-related diseases are chronic neuropathic pain. In some embodiments, pain or pain-related diseases are small fiber neuropathy. In some embodiments, pain or pain-related diseases are non-hospitalized postoperative pain. In some embodiments, pain or pain-related diseases are osteoarthritis. In some embodiments, pain or pain-related diseases are knee osteoarthritis and / or hip osteoarthritis.

[0202] In another aspect, the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention as described herein in the manufacture of a medicament for treating pain and pain-related diseases as described herein.

[0203] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0204] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating pain caused by trauma, pain caused by iatrogenic medical or dental surgery, or pre- or post-operative related pain.

[0205] In one embodiment, there is provided the use of a compound of the invention or 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 idiopathic pain.

[0206] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating neuropathic pain or chronic neuropathic pain, wherein the neuropathic pain or chronic neuropathic pain is selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy.

[0207] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain and chronic inflammatory demyelinating polyneuropathy.

[0208] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the manufacture of a medicament for treating pain or a pain-related disease selected from neuropathic pain, ambulatory postoperative pain, and osteoarthritis. In some embodiments, the pain or pain-related disease is neuropathic pain. In some embodiments, the pain or pain-related disease is chronic neuropathic pain. In some embodiments, the pain or pain-related disease is small fiber neuropathy. In some embodiments, the pain or pain-related disease is ambulatory postoperative pain. In some embodiments, the pain or pain-related disease is osteoarthritis. In some embodiments, the pain or pain-related disease is knee osteoarthritis and / or hip osteoarthritis.

[0209] In one aspect, the invention relates to a method of treating atrial fibrillation as defined herein in a human in need thereof, comprising administering to the human a compound of the invention as described herein or a pharmaceutical composition of the invention. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic renal disease.

[0210] 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 treating atrial fibrillation. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic renal disease.

[0211] In another aspect, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating atrial fibrillation. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic renal disease.

[0212] In another aspect, the invention relates to a compound of the invention or a pharmaceutical composition of the invention for use in therapy.

[0213] Combination therapy

[0214] The compounds and pharmaceutical compositions of the invention disclosed herein can be combined or co-administered with other therapeutic agents, particularly agents that enhance the activity or distribution time of the compounds. The combination therapy of the present invention comprises administering at least one compound of the present invention and using at least one other treatment method, including administering one or more other therapeutic agents.

[0215] As used herein, the term "co-administration" and its derivatives refer to the simultaneous administration or any separate sequential administration of the Na of the present invention described herein. v 1.8 Inhibitory compounds and additional active ingredients. Additional active ingredients include any known compound or therapeutic agent, or a compound or therapeutic agent that exhibits favorable properties when administered to a person in need of treatment. Typically, if administration is not simultaneous, the compounds are administered at times close to each other. In addition, 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.

[0216] Other therapeutic agents that can 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., such as but not limited to duloxetine or amitriptyline), anticonvulsants (i.e., such as but not limited to pregabalin and gabapentin), opioids (i.e., such as but not limited to hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), etc.; and the above-mentioned administration is also determined by a person of ordinary skill in the art. In one aspect, suitable Nav1.7 inhibitors or Nav1.9 inhibitors for use in the present invention include, but are not limited to, those Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0217] Each component of the combination for therapeutic purposes (e.g., a compound or pharmaceutical composition of the invention and an additional therapeutic agent) can be administered orally, intravenously, or parenterally, or a combination thereof. Each component of the therapeutic combination can be administered, but is not limited to, 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. In certain embodiments, each of the same or different routes of administration or a combination of routes of administration is selected from oral, intravenous, or parenteral administration. Example

[0218] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but provide guidance to the skilled person for preparing and using the compounds, compositions and methods of the present invention. Although specific aspects or embodiments of the present invention have been described, the skilled person will appreciate that various changes and modifications may be made without departing from the spirit and scope of the present invention.

[0219] Synthesis Example

[0220] The skilled artisan will appreciate that purification methods (using acidic or basic modifiers) or compound workup procedures (using acidic or basic conditions) may result in the formation of salts of the title compound (e.g., hydrobromic acid, formic acid, hydrochloric acid, trifluoroacetic acid, or ammonium salts of the title compound). The present invention is intended to encompass such salts.

[0221] The final compounds were characterized by GCMS or LCMS (conditions listed below) and NMR. 1 H NMR or 19 FNMR spectra were recorded using a Bruker Avance III 500MHz spectrometer, a Bruker Avance 400MHz spectrometer, and a Varian Mercury Plus-300MHz spectrometer. CDCl3 is deuterated chloroform, DMSO-d6 is hexadeuterated dimethyl sulfoxide, and CD3OD is tetradeuterated methanol. Chemical shifts are reported in parts per million (ppm) from internal standard tetramethylsilane (TMS) or NMR solvents to low magnetic field. The abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=double doublet, dt=double triplet, app=apparent, br=broad peak. J represents the NMR coupling constant measured in Hertz.

[0222] HPLC Method:

[0223] Method A: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm x 30 mm, 1.7 μm column), using a gradient of 1 to 100% MeCN / H2O / 0.1% TFA in 1.85 min at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI.

[0224] Method B: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm×30 mm, 1.7 μm column), using a gradient of 1 to 100% MeCN / H2O / 0.1% 10 mM ammonium bicarbonate / water (adjusted to pH 10 with 25% ammonium hydroxide solution) in 1.85 min at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI.

[0225] In the following experimental descriptions, the following abbreviations may be used:

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232] Example 1: (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 dihydrogen phosphate

[0233] Step 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

[0234]

[0235] To a solution of 7-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazoline-4(1H)-one (which can be synthesized as described in Example 107 of WO2020 / 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 chloromethyl chloroformate (4.00 ml, 44.9 mmol) dropwise, and a white precipitate was immediately formed. The reaction mixture was heated at 85 ° C for 18 hours. Additional chloromethyl chloroformate (2.66 ml, 30.0 mmol) was added and the reaction was heated for another 3 hours. Add extra DABCO (0.420g, 3.74mmol) and chloromethyl chloroformate (2.66ml, 30.0mmol) again, and the reaction is heated for another 19 hours.Finally, chloromethyl chloroformate (1.332ml, 14.98mmol) is added, and the reaction is heated for 4 hours.The reaction mixture is cooled, diluted with more EtOAc, quenched with water, and stirred for 10 minutes.Filter solid, wash with water, and obtain 3.90g required product, which is a light yellow solid.Separate filtrate layer, extract water layer with EtOAc (2x).With saturated NaHCO3 aqueous solution, salt water washing combined organic matter, use Na2SO4 dry and concentrate.Residue is ground with DCM, and light brown solid is obtained, which is further ground with water, and other 1.8g required product is obtained, which is a pale 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) as an off-white solid. HPLC / MS 1.24 min (Method B), [M+H] + 498.0. 1 H NMR(DMSO-d6,400MHz)δ8.10(d,1H,J=7.8Hz),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).

[0236] Step B: Di-tert-butyl ((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) phosphate

[0237]

[0238] 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, at which time a gel formed. The reaction mixture was cooled and quenched with water, at which time a precipitate formed. The solid was filtered and washed with water to give di-tert-butyl ((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)phosphate (7.24 g, 10.24 mmol, 82% yield) as a light yellow solid. HPLC / MS 1.36 min (Method B), [M+H] + 672.2. 1 H NMR(DMSO-d6,400MHz)δ8.10(d,1H,J=8.3Hz),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=12.7,18.1Hz),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).

[0239] Step C: (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 dihydrogen phosphate

[0240]

[0241] A slurry of di-tert-butyl ((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)phosphate (7.20 g, 10.18 mmol) in acetone (70 mL) and water (56.0 mL) was heated at 50° C. for 6 hours (solution purged). The reaction mixture was allowed to reach room temperature and stirred for an additional 20 hours. The volatiles were evaporated in vacuo at 35 °C and the aqueous portion was freeze dried to give an off-white solid which was triturated with DCM:ether (1:3) to give (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 dihydrogen phosphate (5.10 g, 8.66 mmol, 85% yield) as an off-white solid. HPLC / MS 0.78 min (Method B), [M+H] + 560.2. 1 H 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 H 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).

[0242] 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

[0243] Step A: 2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinic acid

[0244]

[0245] 2-Chloro-5-(trifluoromethyl)nicotinic acid (5g, 22.17mmol), p-TsOH (1.265g, 6.65mmol) and pyridine (1.793ml, 22.17mmol) were added to a mixture containing 2-methyl-4-(trifluoromethoxy)aniline (4.24g, 22.17mmol) in water (50ml). The reaction mixture was heated at 95°C for 4 days. The reaction mixture was cooled to room temperature, then diluted with 150mL of water and stirred for 1 hour. The solid was filtered and washed with water (3x25mL), dried under vacuum to give 2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinic acid (6.886g, 17.20mmol, 78% yield) as an orange-yellow solid. HPLC / MS 0.93min (Method B), [M+H] + 381.0. 1 H NMR(DMSO-d6,400MHz)δ14.16(br s,1H),10.55(s,1H),8.69(dd,1H,J=1.0,2.4Hz),8.42(d,1H,J=2.4Hz),8. 15(d,1H,J=9.3Hz),7.32(s,1H),7.24(dd,1H,J=2.2,9.0Hz),2.32(s,3H).

[0246] Step B: N-(6-methoxy-2,5-dimethylpyridin-3-yl)-2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinamide

[0247]

[0248] To 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 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 x 150 mL). The combined organics were washed with water (3 x 100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with DCM to give 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 to 15% EtOAc / heptane as eluent to give an additional 2.1 g of the desired product as an off-white solid. The two batches were combined and dissolved in EtOAc and concentrated to give 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-d6,400MHz)δ10.87(s,1H),10.42(s,1H),8.67(s,2H),8.19(d,1H,J=8.8Hz),7.48(s,1H),7.3-7.3(m,1H),7.23(br d,1H,J=8.8Hz),3.90(s,3H),2.33(s,3H),2.28(s,3H),2.14(s,3H).

[0249] 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

[0250]

[0251] 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) was 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 hours, 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% to 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-d6,400MHz)δ8.62(d,1H,J=1.5Hz),8.34(d,1H,J=2.4Hz),7.4-7.5(m,3H),7.31(br d,1H,J=8.3Hz),5.0-5.8(m,2H),3.89(s,3H),2.30(br s,3H),2.25(s,3H),2.12(s,3H).

[0252] 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

[0253]

[0254] 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 to 6 N in IPA) (42.8 mL, 214 mmol). The reaction mixture was heated at 90 °C for 3 hours, then 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 to 10% MeOH / DCM as 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, 400MHz) δ11.73 (s, 1H), 8.60 (d, 1H, J = 2.0Hz), 8.31 (d, 1H, J = 2. 0Hz),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).

[0255] 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

[0256]

[0257] To 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) to form a white precipitate. The reaction mixture was heated at 85°C for 19 hours, additional chloromethyl chloroformate (1.326 ml, 14.91 mmol) was added and stirred at 85°C for another 3 hours, followed by additional chloromethyl chloroformate (0.331 ml, 3.73 mmol) and stirred at 85°C for another 1 hour. 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 NaHCO3 aqueous solution, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (CombiFlash, 80 g column) eluting with 100% heptane for 5 minutes followed by 10 to 60% EtOAc / heptane 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 (4.0 g, 7.13 mmol, 96% yield) as a white solid. HPLC / MS 1.31 min (Method B), [M+H] + 561.1. 1 H NMR (DMSO-d6, 400MHz) δ8.61 (s, 1H), 8.32 (d, 1H, J = 2.4Hz), 7.4-7.5 (m, 3H), 7.31 (br d,1H,J=8.3Hz),4.9-6.4(m,4H),2.41(s,3H),2.24(s,3H),2.0-2.0(m,3H).

[0258] Step F: Di-tert-butyl ((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) phosphate

[0259]

[0260] 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 potassium 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 heated at 70° C. for 3 hours. The reaction mixture was cooled and quenched with water (300 ml) when a white precipitate formed. The slurry was stirred vigorously for 1 hour. The solid was filtered and washed with water to give di-tert-butyl ((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)phosphate (5.086 g, 6.72 mmol, 86% yield) as an off-white fine powder. HPLC / MS 1.41 min (Method B), [M+H] + 735.1. 1 H NMR(DMSO-d6,400MHz)δ8.61(br s,1H),8.32(d,1H,J=2.4Hz),7.4-7.5(m,3H),7.31(br d,1H,J=7.8Hz),5.84(br d,2H,J=5.9Hz),4.8-5.7(m,2H),2.36(s,3H),2.24(s,3H),2.00(br s,3H),1.41(s,18H).

[0261] Step 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

[0262]

[0263] A slurry of di-tert-butyl ((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) phosphate (5.0 g, 6.81 mmol) in acetone (50 mL) and water (40 mL) was heated at 50° C. for 26 hours. The clear reaction mixture was cooled, concentrated under reduced pressure at 50° C., and dried in a vacuum oven at 45° C. overnight to give 4.2 g of an off-white glass solid. The solid was triturated with ether to give 3.4 g of a white solid which was triturated 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 (3.10 g, 4.83 mmol, 71% yield) as a white solid. 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); 1 H 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).

[0264] Example 3: (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 dihydrogen phosphate

[0265] Step A: 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3,4-difluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0266]

[0267] To a solution of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[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) was added chloromethyl chloroformate (0.080 ml, 0.899 mmol) dropwise under nitrogen and stirred at room temperature for 2 hours then at 60° C. for 18 hours. Additional 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. Additional 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% to 50% (3:1 EtOAc:EtOH) / heptane) to give the title compound (110 mg, 0.221 mmol, 61% yield). 1 H NMR (DMSO-d6, 501MHz): 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=18.4Hz,1H,H-6),6.44(d,J=9.8Hz,1H,H-18),5.57-6.32(m,2H,H-20),4.8 5-5.56(m,2H,H-15),2.31-2.48(m,3H,H-21),2.23(s,3H,H-1).MS(m / z)499(M+H + ).

[0268] Step B: Di-tert-butyl ((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) phosphate

[0269]

[0270] 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-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (0.091 g, 0.182 mmol) and potassium 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 heated at 70 °C for 2 hours. Additional DMF (0.5 ml) was added as the reaction thickened. 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 (3x). 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% to 50% (3:1 EtOAc:EtOH) / heptane) to afford the title compound (95 mg, 0.141 mmol, 77% yield). 1 H 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-(tert-butyl)).

[0271] Step C: (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 dihydrogen phosphate

[0272]

[0273] To a solution of di-tert-butyl ((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) phosphate (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 stirred at 70°C for 1.5 hours. The solvent was then concentrated and the reaction was purified at ambient temperature by reverse phase chromatography on an XSELECT CSH C18 column (150 mm×30 mm, id5 μm packing diameter) using 0.1% formic acid / acetonitrile / 0.1% formic acid / water as eluent to give the title compound (46 mg, 0.081 mmol, 61% yield). 1 H NMR (DMSO-d6, 400 MHz) δ8.05 (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 hydroxyl proton exchange MS (m / z) 559 (MH) - .

[0274] Example 4: (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

[0275] Step A: 4-Chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid

[0276]

[0277] To 1-bromo-3,4-difluoro-2-toluene (8.52 g, 41.1 mmol) in anhydrous degassed 1,4-dioxane (176 ml) was 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) under nitrogen. The reactants were stirred at 95 °C for 3 days. The brown suspension was cooled and 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 (3x25mL), and dried in air under vacuum to give 4-chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluorobenzoic acid, cesium salt (2.78g, 5.58mmol, 17.6% yield) as a tan orange solid. The resulting diatomaceous earth filter cake containing additional product was transferred to a 1L beaker, stirred with 200mL water at 25°C and the pH was adjusted to 4 to 5 with 1NHCl, at which time DCM (500mL) was added. The diatomaceous earth mixture was filtered, and the solid was kept to further isolate the product. The filtrate layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at 40 ° C to the desired product as an orange-yellow solid, 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 diatomaceous earth filter cake solid from above was transferred to a 1L beaker, MeOH (400 mL), MeCN (100 mL) and DCM (50 mL) were added, and the mixture was stirred at 25 ° C for 1 hour. The solids were collected by vacuum filtration and rinsed with MeOH (4×25 mL). The filtrate was concentrated at 40 ° C to a brown solid as an additional desired product, 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 H NMR (400MHz, DMSO-d6) δ12.16 (s, 1H), 7.74 (d, J = 10.3Hz, 1H), 7.19 (q, J = 9.3Hz, 1H), 7.13-7.07 (m, 1H), 6.91 (d, J = 6.4Hz, 1H), 2.16 (d, J = 2.4Hz, 3H).

[0278] Step B: 4-Chloro-2-((3,4-difluoro-2-methylphenyl)amino)-5-fluoro-N-(6-methoxy-2-methylpyridin-3-yl)benzamide

[0279]

[0280] 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) was added 6-methoxy-2-methylpyridin-3-amine (4.46 g, 32.3 mmol) and HATU (11.78 g, 31.0 mmol), followed by portionwise addition of DIEA (13.53 ml, 77 mmol) over 30 min to give a dark brown solution. This was stirred at 25 °C for 5 min and combined with another batch (2.70 g, 6.18 mmol crude product) for work-up and purification. Water (320 mL) was added portionwise to the crude reaction mixture with stirring and the mixture was extracted with EtOAc (400 mL, then 100 mL). The combined organic layers were washed with water (2 x 200 mL) followed by brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to a brown oil at 40 ° C in vacuo. 10 mL of DCM was added to this oil to form a granular solid, 1: 1 DCM: heptane (100 mL) was added and stirred for 3 hours to decompose the solid. The solid was collected by vacuum filtration, the filter cake was rinsed with 10% DCM / heptane (4x10 mL), and dried overnight under vacuum to give 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, followed by addition of 1: 1 DCM: heptane (100 mL) and stirred for 1 hour to decompose the solid. The solid was collected by vacuum filtration, rinsed with heptane (4x10 mL), and dried in air under vacuum to give additional 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, eluted with 0 to 25% EtOAc / heptane, 10 min gradient, 125 mL / min). The pure fractions were 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, 11.88% yield) as a bright orange solid. HPLC / MS 1.32 min (Method A), [M+H] + 436.0. 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.27(s,1H),7.96(d,J=10.3Hz,1H),7.60(d,J=8.8Hz,1H),7.28(q,J=9.3Hz,1 H),7.18-7.08(m,1H),6.92(d,J=6.8Hz,1H),6.69(d,J=8.3Hz,1H),3.85(s,3H),2.35(s,3H),2.12(d,J=2.0Hz,3H).

[0281] 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

[0282]

[0283] 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) was 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 hour to give an orange gum upon completion. Saturated sodium bicarbonate (25 mL) was added, the organic layer was separated and the aqueous solution was extracted with 2 x 25 mL EtOAc. The combined organics were combined, dried over anhydrous MgSO4 and concentrated in vacuo to a brown foam. This was combined with another batch of crude product (1.78 g, 3.99 mmol) for purification. This combined solid was dissolved in 20 mL DCM and purified via Isco CombiFlash Rf (0% to 50% in EtOAc / heptane; 330 g column, 25 min gradient). Pure fractions were collected and the product was isolated by vacuum concentration 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 based on two batches). HPLC / MS 1.31 min (Method B), [M+1] + 448.1. 1HNMR(DMSO-d6,400MHz)δ7.79(d,1H,J=9.3Hz),7.59(br d,1H,J=7.8Hz),7.3-7.5(m,1H),7.16(br d,1H,J=2.4Hz),6.71(d,1H,J=9.3Hz),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=1.5Hz).

[0284] Step D: 7-Chloro-1-(3,4-difluoro-2-methylphenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-yl)-2,3-dihydroquinazolin-4(1H)-one

[0285]

[0286] 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 in isopropanol) in isopropanol (255 ml) was heated to 90° C. under a condenser for 1 hour, at which time 1,2-dichloroethane (85 ml) was added and the solution was heated at 90° C. for 20 hours. The reaction was cooled and the solvent removed in vacuo to give a white solid (9.9 g). The solid was dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate solution, the organics were 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-yl)-2,3-dihydroquinazolin-4(1H)-one as a white solid. (8.55 g, 19.7 mmol, 77% yield). HPLC / MS 1.08 min (Method B), [M+1] + 434.1. 1 H NMR(DMSO-d6,400MHz)δ11.75(br s,1H),7.77(d,1H,J=9.3Hz),7.35(br dd,2H,J=10.3,19.1Hz),7.13(br s,1H),6.4-6.8(m,1H),6.17(br d,1H,J=9.3Hz),4.7-5.5(m,2H),2.0-2.1(s,6H).

[0287] 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

[0288]

[0289] To 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 (4.6 g, 10.60 mmol) and DABCO (1.784 g, 15.91 mmol) in ethyl acetate (96 ml) and N,N-dimethylformamide (DMF) (9.64 ml) was added chloromethyl chloroformate (3.77 ml, 42.4 mmol) and heated to 90° C. for 36 hours, then at 25° C. for a total of 3 days. Additional chloromethyl chloroformate (3.77 ml, 42.4 mmol) was added and heated at 90° C. for 2 hours. The reaction was cooled and 100 mL of water and 50 mL of brine were added. The product was extracted into 100 mL EtOAc, the organic layer was separated, the aqueous layer was extracted with 75 mL EtOAc, the combined organic layers were washed with brine (2×), saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a yellow solid (4.8 g). The solid was ground with 10 mL DCM to give a white solid (3 g). The filtrate was filtered to give a second batch of product. 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, and the residue was dissolved in 1:1 hot EtOAc: MeOH and pre-absorbed on silica gel. The residue was purified via Isco CombiFlash Rf (50% to 100% in EtOAc / heptane; 40 g column, 20 min gradient). The pure fractions were combined and concentrated in vacuo to give the additional title compound as a white solid (500 mg 1.04 mmol, 9.8% yield). HPLC / MS 1.25 min (Method B), [M+1] + 482.1. 1 H NMR (DMSO-d6, 400MHz) δ7.78 (d, 1H, J = 9.3Hz), 7.2-7.5 (m, 2H), 7.16 (br dd,1H,J=3.9,8.3Hz),6.4-6.8(m,1H),6.41(d,1H,J=9.8Hz),5.5-6.3(m,2H),4.7-5.4(m,2H),2.2-2.5(m,3H),2.20(d,3H,J=2.0Hz).

[0290] Step F: Di-tert-butyl ((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) phosphate

[0291]

[0292] 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 heated at 70°C for 1 hour. The slightly gummy mixture was quenched with 40 mL of water and extracted into 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 a yellow semisolid. The solid was purified via Isco CombiFlash Rf (0% to 20% (3:1 EtOAc / EtOH) in DCM, 80 g silica column, 20 min gradient). Pure fractions were combined and concentrated in vacuo to afford di-tert-butyl ((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)phosphate as a solid. HPLC / MS 1.37 min (Method B), [M-2 t Bu] + 544.0. 1 H NMR (DMSO-d6, 400MHz) δ7.78 (d, 1H, J = 9.3Hz), 7.3-7.5 (m, 2H), 7.16 (br d,1H,J=1.0Hz),6.4-6.8(m,1H),6.38(d,1H,J=9.8Hz),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).

[0293] Step G: (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

[0294]

[0295] Di-tert-butyl ((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)phosphate (3.36 g, 5.12 mmol) was heated in acetone (26 ml) and water (26 ml) at 50°C for 18 hours. The reaction was cooled to give a colorless solution which was evaporated in vacuo at 40°C to a white foamy solid which was dried under high vacuum to give (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 (2.6 g, 4.78 mmol, 93% yield). HPLC / MS 0.73min (Method B), [M+H] + 544.0. 1 H NMR(DMSO-d6,400MHz)δ11.0-12.2(m,2H),7.78(d,1H,J=9.3Hz),7.38(br d,2H,J=9.8Hz),7.1-7.2(m,1H),6.5-6.8(m,1H),6.37(d,1H,J=9.8Hz), 5.6-5.8(m,2H),4.6-5.5(m,2H),2.2-2.4(m,3H),2.20(d,3H,J=2.4Hz).

[0296] Example 5: (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 dihydrogen phosphate

[0297] 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

[0298]

[0299] 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 ml) was added chloromethyl chloroformate (2.164 ml, 24.34 mmol) dropwise via addition funnel under nitrogen and heated to 75 °C for 19 h. The reaction was cooled, quenched with water and the layers separated. The aqueous layer was back extracted with EtOAc (2x) and the combined organics were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (Isco, 300 g column, 0% to 50% (3:1 EtOAc:EtOH) / heptane) to afford the title compound (3.88 g, 8.19 mmol, 67% yield). 1 H NMR(DMSO-d6,400MHz)δ7.78(d,1H,J=9.3Hz),7.47(d,1H,J=9.8Hz),7.3-7.4(m,2H),7.1-7.2(m,1H),6.42(d, 1H,J=9.8Hz),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) + .

[0300] Step B: Di-tert-butyl ((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) phosphate

[0301]

[0302] 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 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 (3x). 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% to 20% (3:1 EtOAc:EtOH) / DCM) to afford the title compound (3.52 g, 5.35 mmol, 70% yield). 1 H NMR (DMSO-d6, 400MHz) δ7.78 (d, 1H, J = 8.8Hz), 7.45 (d, 1H, J = 9.8Hz), 7.3-7.4 (m, 2H), 7.16 (br s,1H),6.3-6.6(m,2H,J=9.8Hz),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=2.4Hz),MS(m / z)638(M+H) + .

[0303] Step C: (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 dihydrogen phosphate

[0304]

[0305] A solution of di-tert-butyl ((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)phosphate (3.47 g, 5.44 mmol) dissolved in acetone (40 ml) and water (30 ml) was heated to 50 °C for 16 h and stirred at room temperature for 6 h. The solvent was concentrated and then pumped under high vacuum to give the title compound (2.74 g, 5.16 mmol, 95% yield). 1H NMR (DMSO-d6, 400MHz) δ7.78 (d, 1H, J = 9.3Hz), 7.44 (d, 1H, J = 9.8Hz), 7.3-7.4 (m, 2H), 7.18 (br d,1H,J=6.8Hz),6.3-6.5(m,2H,J=9.8Hz),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) + .

[0306] Table 1.

[0307]

[0308]

[0309]

[0310] Table 1A.

[0311]

[0312]

[0313] Example 6: Preparation of 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

[0314] 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 (Compound Example No. 4) was prepared and characterized by X-ray powder diffraction (XRPD) using a Cu radiation source.

[0315] Route 1

[0316] A solution 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 (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 allowed to stand at 25 °C for 4 days. A white solid was formed and the solvent was removed by evaporation to give (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 (20.0 mg, 0.037 mmol, 57.1% yield) as a white solid showing some crystalline features by XRPD ( Figure 1 ).

[0317] Route 2

[0318] A solution 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 (875 mg, 1.61 mmol) in ethyl acetate (400 μl) was prepared by heating to 65°C, followed by the addition of tert-butyl methyl ether (10 drops, 401 μl), leaving to stand, and slowly cooling to 25°C over 4 days. The solid formed was filtered, dried in air for 18 hours, and then dried in a high vacuum oven at 60°C for 18 hours. XPRD pattern ( Figure 2 ) showed crystalline characteristics of the desired product (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 (0.500 g, 0.919 mmol, 57.1% yield). HPLC / MS 0.74 min (Method B), [M+H] + 544.0. 1 H NMR(DMSO-d6,400MHz)δ11.0-12.2(m,2H),7.78(d,1H,J=9.3Hz),7.38(br d,2H,J=9.8Hz),7.1-7.2(m,1H),6.5-6.8(m,1H),6.37(d,1H,J=9.8Hz), 5.6-5.8(m,2H),4.6-5.5(m,2H),2.2-2.4(m,3H),2.20(d,3H,J=2.4Hz).

[0319] Seed preparation

[0320] To di-tert-butyl ((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) phosphate (8.5 g, 12.957 mmol, 1 eq) was charged acetonitrile (59.5 mL, 0.218 M, 7 vol eq) and water (8.5 mL, 1.524 M, 1 vol eq). The mixture was warmed to Tr=50°C (Tj=53°C to 54°C) and stirred until a solution was obtained. Subsequently, acetonitrile (34 mL, 0.381 M, 4 vol eq) was charged while maintaining the mixture temperature in the range of 45°C-50°C. The mixture was then cooled to 15°C at a rate of 0.4°C / min and stirred overnight. The mixture was then further cooled to 0°C at a rate of 0.3°C / min and stirred for 2 h. The obtained suspension was filtered and washed with acetonitrile (2 x 3 volumes). The wet cake was then dried under vacuum at room temperature to give 5.95 g of anhydrous crystalline solid, which was identified by XRDP ( Figure 5 The obtained crystalline solid was used as seed in the subsequent procedures (Scheme 3 and Scheme 4).

[0321] Route 3

[0322] (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 was mixed with 7.4 volume equivalents of acetone and 2.6 volume equivalents of DMSO at 25°C. 0.3 volume equivalents of DMSO were then added and the mixture was stirred until completely dissolved. Clarification filtration was then performed. The following feeds were performed based on the dissolved compound. Three volume equivalents of water were added to the clear solution, followed by 1.9 wt% of the crystalline compound as seed. The mixture was then mixed for about 15 h. Another 3 volume equivalents of water were added, followed by 1.2 wt% of the crystalline compound as seed. The mixture was then mixed for 40 min, followed by the addition of 8.26 volume equivalents of water over 6 h. The mixture was then aged for 19 h to give a white suspension. The suspension was then filtered under vacuum and the filter cake was washed sequentially with 3×3 volume equivalents of water / acetone 2:1 (v:v) as the displacement wash liquid. The wet filter cake was then dried under vacuum at approximately 50° C. with a slight air purge until constant weight was obtained to give crystalline (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 ( Figure 3 ).

[0323] Route 4

[0324] (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 was mixed with 2.5 volume equivalents of acetone and 2.5 volume equivalents of DMSO at 25°C until completely dissolved. 5 volume equivalents of water were then added, followed by 16 wt% of the crystalline compound as a seed, as a suspension of 10 volume equivalents of acetone / DMSO / water 1:1:2 (v:v:v) based on the mass of the seed. The mixture was then mixed for 18 hours to obtain a white suspension. The suspension was then vacuum filtered and the filter cake was washed with 3×3 volume equivalents of acetone as a displacement wash. The wet cake was then dried under vacuum at approximately 50°C until constant weight was obtained to give crystalline (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. The XRPD pattern is shown in Figure 4 The characteristic peaks or diffraction angles (2θ) of the XRPD pattern are listed in Table 2. The XRPD was obtained using a Rigaku Miniflex X-ray diffractometer with a Cu source using the following measurement parameters:

[0325] Starting position (°2θ) 5.0000

[0326] End position (°2θ) 40.0000

[0327] Step size 0.0200

[0328] Scan step time (s) 0.3478

[0329] Anode material Cu

[0330] K-Alpha1 1.54060

[0331] K-Alpha2 1.54443

[0332] Generator settings 15mA, 40kV

[0333] Table 2: Characteristic peaks and d-spacings

[0334]

[0335]

[0336] Bioassay

[0337] Bioassay 1: Na v 1.8 Inhibitory activity

[0338] Will express human Na v 1.8 Human Na v β1 and human TREK1 (HEK293-Na v 1.8) were grown in a T150 cell culture flask in a 37°C, 5% CO2 incubator. When the confluence in the T150 cell culture flask reached 80% to 90%, HEK293-Na v 1.8 Subculture every 2 to 3 days.

[0339] The pharmacological evaluation of the compounds of the present invention was performed using the QPatch 48HTX electrophysiology platform. HEK293-Na was prepared on the day of use by the following v 1.8 Cells: Remove medium, wash in DPBS, add Accutase (2 mL to cover the surface, aspirate 1 mL, then incubate at 37°C for 1 to 2 minutes), then add CHO-SFMII to stop enzymatic digestion to obtain 3×10 6 cells / mL of suspension.

[0340] The compounds of the 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, with a NaOH osmotic pressure (Osmolality) of 300 mOsM / L. An intracellular solution of the following composition was used: CsF (115 mM), CsCl (20 mM), NaCl (5 mM), EGTA (10 mM), HEPES (10 mM), sucrose (20 mM), pH 7.2, with a CsOH osmotic pressure of 310 mOsm / L.

[0341] The voltage clamp mode was used in the QPatch 48HTX system, using a semi-inactivation voltage protocol (V 1 / 2 ) Determine in Na v 1.8 Pharmacological activity of the compounds of the present invention on ion channels. Using a V having the following voltage steps 1 / 2Protocol: A holding voltage of -100 mV was established, followed by a 20 ms voltage step down to 0 mV (P1), followed by an 8 s hold at an inactivation voltage step of -46 mV, followed by a step to -100 mV for 20 ms, followed by a 20 ms step to 0 mV (P2), followed by a return to a holding voltage of -100 mV. This voltage protocol was repeated every 15 s, and the current amplitude was quantified at the P2 step throughout the recording. Fitting of a 4 to 6 point dose-response curve allowed the determination of the 50% inhibitory concentration (IC 50 ) to determine the inhibition of the measured current amplitude by the compounds of the present invention. The P2 current was standardized according to the measurements performed at baseline (Baseline, vehicle only), after the compound (Input, at each test concentration) and after the positive reference compound (FullResponse, achieving complete blockade), fitting the following equation:

[0342]

[0343] To assess the current drop during the experiment, vehicle-only wells were used and the vehicle-only (nI VEH ). To correct the compound response to the drop, the current was corrected according to the following formula:

[0344]

[0345] The compound inhibition was fitted according to the following Hill equation to estimate the half maximal inhibitory concentration (IC 50 )

[0346]

[0347] Where Y is relative to vehicle control (equivalent to n. RD_校正 ), I is the concentration of the test compound, IC 50 is the concentration of the test compound that inhibits the sodium current by 50%, and h is the Hill coefficient.

[0348] The exemplary compounds shown in Tables 1 and 1A herein have activity on the Nav1.8 sodium channel as measured using the assays described herein and as shown in Table 3 below.

[0349] Each of the compound examples of the present invention listed in the following table was tested individually in at least one of the exemplary salt or free base forms. Unless otherwise indicated, the test compound examples of the present invention exhibited pharmacological activity Na v 1.8 pIC 50 (Qpatch)>5.0. On the other hand, the test compound embodiments of the present invention exhibit pharmacologically active Na v 1.8 pIC 50(Qpatch)>6.0.

[0350] Table 3. Results of Biological Assay 1

[0351]

[0352]

[0353] Biological Assay 2: CAD Solubility

[0354] Dynamic solubility was measured using a charged aerosol detector (CAD). The aqueous dynamic solubility of pH 7.4 was determined by measuring the solute concentration in the solution after precipitation from the DMSO stock solution. The DMSO stock solution was diluted 20 times with phosphate buffered saline (PBS) of pH 7.4, and the solubility of the compound was measured by HPLC-CAD after equilibration at room temperature for 1 hour. The calibration standards of ketoconazole and primidone were prepared by serial dilution in a concentration range of 0.016 to 4.5 mg / ml in DMSO to produce a calibration curve for determining the solubility of the compound, 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, which is incorporated herein by reference. The CAD solubility of the prodrug compound of the present invention and the corresponding parent compound was measured as described above, and the results are shown in Table 4 below.

[0355] Table 4. Results of Biological Assay 2

[0356]

[0357] Bioassay 3: Rat IV / PO Study

[0358] In vivo rat pharmacokinetic studies were conducted to determine whether the prodrug compounds of the present invention are converted into their respective parent compounds after administration. The rat pharmacokinetic study was conducted in a crossover design over two study days with a one-day recovery period between each study day. Three male double cannulated (femoral vein and carotid artery) Han Wistar rats were used for the study. Each rat was also implanted with a gastric catheter for oral administration. Rats were administered 1 mg / kg by 60-minute intravenous (IV) infusion (femoral vein cannulation), followed by oral administration of 2 mg / kg by gastric cannulation, with a dosing interval of 48 hours. Dosing solutions of the compound of Example 4 were prepared in 20% Cavitron / 5% DMSO / 75% water (IV) and in 6% Cavitron / 5% DMSO / 89% water (PO) without pH adjustment. The dosing solution was filtered using a 0.22 μm filter. The pH value of the final dosing solution was 6.0.

[0359] During the intravenous study leg, blood samples were collected from the carotid artery catheter at 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, blood samples were collected before dosing and at target times of 15, 30, 60, 90, 120, 180, 240, 360, 480, 720 and 1440 minutes after oral dosing. Blood samples (100 μL) were mixed with 100 μL of phosphatase inhibitors, and 50 μL aliquots of the blood and inhibitor mixture were transferred to non-heparinized tubes and stored at approximately -80°C until analysis. The concentration in the filtered dosing solution was confirmed by preparing stepwise dilutions first into 50% acetonitrile in water with 0.1% formic acid and then into heparinized male Wistar Han blood: inhibitor to achieve a determined nominal concentration. Triplicate 50 μL aliquots were removed, frozen and stored at approximately 80°C until analysis by LC-MS / MS as described below. The compound of Example 4 and the corresponding parent compound of Example 4A were quantified using LC-MS / MS in biological samples generated in the in vivo studies described above.

[0360] The samples were prepared by protein precipitation and then LC-MS / MS analysis was performed using positive mode ionization on a set of calibration standards of the compound prepared in the same matrix. The pharmacokinetic parameters for this study were derived from the concentration versus time curves. The key pharmacokinetic parameters of the compound of Example 4, such as AUC 0-∞ (extrapolated area under the plasma concentration-time curve), AUC 0-t(area under the plasma concentration-time curve to the last time point at which the drug can be quantified), Cmax (maximum concentration), Tmax (time to reach Cmax), CL (systemic blood clearance), Vdss (steady-state volume of distribution), MRT (mean residence time), and t 1 / 2 (half-life). Determine the key pharmacokinetic parameters of the parent compound Example 4A, such as AUC 0-∞ , AUC 0-t , Cmax, Tmax, MRT and t 1 / 2 (half-life). Descriptive statistics for pharmacokinetic parameters, including mean and standard deviation (SD), were calculated using Microsoft Excel. The data are shown in Tables 5A and 5B below. Data are reported as mean ± SD (N = 3).

[0361] Table 5A. Results of Biological Assay 3 (Prodrug Compounds)

[0362]

[0363]

[0364] Table 5B. Results of Biological Assay 3 (parent compound)

[0365]

[0366] b Because of the differences in the IV group, the values ​​are presented separately

[0367] c NR means "not recorded"

[0368] d Data from Example 4A based on the dosage of the prodrug of Example 4

[0369] Biological detection 4: Artificial patch clamp electrophysiological detection

[0370] The pharmacological activity of Example 4A and Example 5A compounds (active parent compounds of prodrug Example 4 and Example 5, respectively) was studied using a patch clamp electrophysiology method using a cell system overexpressing human Nav1.8 in HEK293 cells. Using this method, Nav1.8 can be activated by modulating the plasma membrane voltage, and then channel function (Na+ conduction) can be directly quantified. The ability of Nav1.8 inhibitors to block channel function in this system is a measure of target binding and inhibition.

[0371] method

[0372] Cell preparation: HEK293 cells overexpressing human Nav1.8 (BIOCAT124824) were grown in a medium (DMEM / F12 containing 10% FBS, 2mM GlutaMAX, 0.1mM NEAA, 400mg / ml G418, 100mg / ml hygromycin-B, and 0.625mg / ml puromycin) at 37°C and 5% CO2. When the cell confluence reached about 80%, the cells were passaged every 2-3 days.

[0373] Electrophysiological Recording Solution Preparation: Extracellular and intracellular solutions were prepared and used for voltage clamp recordings in whole-cell patch clamp studies as follows:

[0374] 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); pH was adjusted to 7.4 with NaOH, and osmolarity was adjusted to 310 mosM.

[0375] 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); pH was adjusted to 7.3 with CsOH and osmolarity was adjusted to 295 mosM.

[0376] Whole-cell patch-clamp study 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 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 resistance of the recording electrode was 1–1.5 MΩ when filled with internal solution, and the access resistance was typically <3 MΩ after the whole-cell configuration. Voltage errors were minimized by 80–90% series resistance compensation. Extracellular solution was continuously perfused into the cell under gravity at a rate of 0.5 ml / min, and the solution was pumped with a pump (Watson-Marlow 120U / DM2 peristaltic tube pump, Marlow, United Kingdom) at 35 rpm to maintain a stable liquid level. Drug delivery was performed using a manually controlled fast-step perfusion system (SF-77B, Warner Instruments).

[0377] During each recording, 0.1% DMSO was perfused for 2 min to monitor baseline, and compounds were applied for 6 min to ensure that inhibition reached a steady state.

[0378] Voltage clamp recording protocol: Compound effects were tested using a single pulse resting protocol in which cells were depolarized from a holding voltage of -120 mV to 0 mV for 50 ms. Peak current amplitudes were measured from activation currents at 0 mV. Stimuli were applied every 20 seconds.

[0379] Test compounds: Compounds were dissolved in DMSO at a maximum concentration of 10 mM. For dose response studies, stock solutions ranging from 0.1 mM to 10 mM were prepared in DMSO. Different working concentrations were generated in the extracellular solution by diluting 1:1000 from each stock solution. For the vehicle group, 0.1% DMSO in the extracellular solution was used as a negative control.

[0380] Nav1.8 current amplitude measurement and normalization: The Nav1.8 peak current induced by a 0 mV test pulse was measured and analyzed using Clampfit 10.6 software (Molecular Devices, USA). In each recording, all peak current amplitudes (I) obtained at different time points were normalized to the first data point (I0) at time zero to obtain the I / I0 value.

[0381] Compound inhibition analysis: The compound inhibition effect is calculated according to the following formula:

[0382] % inhibition = ([I / I0] ctrl -[I / I0] cmpd ) / [I / I0]ctrl*100

[0383] [I / I0] ctrl is the average I / I0 of the last 3 scans during the baseline period when 0.1% DMSO was applied; [I / I0] cmpd is the average I / I0 of the last 3 scans when inhibition reached steady state during compound application.

[0384] Statistics and data visualization in GraphPad Prism: To generate graphs, normalized data from individual recordings and calculated inhibition rates were pasted into Prism 8.0 or 9.0 (Graphpad Software, San Diego, California, USA). Dose-response curves were fitted using the four-parameter Hill equation: E = (E max -E min ) / [1+(IC 50 / C)h]+Emin, where E is the response, E max and E minare the maximum and minimum responses, respectively, for E max No restrictions, E. min The limit is zero. IC 50 is the concentration corresponding to the half-maximal inhibitory effect, C is the drug concentration, and h is the Hill coefficient or Hill slope.

[0385] result

[0386] The potency of Compound Example 4A was tested in four separate experiments using three different synthetic batches, and the potency of Compound Example 5A was tested in a single experiment. Table 6 below reports the measured IC values ​​for each compound. 50 (Concentration at which 50% Nav1.8 inhibition is observed) The results indicate that the compound of Example 4A is a more potent inhibitor of Nav1.8 than the compound of Example 5A.

[0387] Table 6: Results of artificial patch clamp electrophysiology assays

[0388] Compound <![CDATA[IC 50 (nM)]]> <![CDATA[Example 4A a > 0.8±0.2 <![CDATA[Example 5A b > 2.2

[0389] a The reported results are the average of four independent experiments performed using three different batches of synthetic compounds.

[0390] b The reported results are from a single experiment.

Claims

1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, which is a pharmaceutically acceptable salt selected from the following compounds: in: R 1 -P(O)(OH)O - M + ,-PO(O - )2·2M + or-PO(O - )2·D 2+ ; Each M + are independently pharmaceutically acceptable monovalent cations; and D 2+ It is a pharmaceutically acceptable divalent cation.

3. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

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 its tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

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

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

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

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

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

17. A compound according to any one of claims 1 to 8 or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a 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 its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12 in the preparation of a medicament for treating pain or pain-related diseases.

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

20. The method of claim 13, the compound for use according to claim 16 or the use according to claim 18, wherein the pain or pain-related disorder is neuropathic pain, ambulatory postoperative pain or osteoarthritis.

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