Process and intermediates for the preparation of thiazole derivatives useful for the treatment of herpes virus infections

Abstract

The application relates to methods and intermediates for synthesizing the thiazole derivative Coumpound (1) useful in treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection.

Description

SYNTHETIC PROCESSESFIELD OF THE DISCLOSURE

[0001] The present disclosure relates to methods of synthesizing a particular compound useful in treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection.BACKGROUND

[0002] Human herpes viruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing life-long infections in humans. This is accomplished by their ability to exist in the host either as a symptom free latent infection, where the virus lies dormant or, following activation, as a lytic infection with associated symptoms. These viral infections have widespread, worldwide prevalence and it is notable that over 90% of all humans are chronically infected with more than one human herpes virus.

[0003] Human herpes viruses are classified into three subfamilies (a, p and y) based upon their biological characteristics and the family consists of eight members, i.e., Herpes Simplex Virus subtype type 1 and 2 (HSV1 , HSV2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and Human Herpes Viruses 6-8 (HHV 6-8).

[0004] HSV1 and 2 infections can cause disease in immune competent individuals. Both subtypes cause cutaneous genital / anal and oro-labial / nasal cavity (cold sore) lesions, although HSV2 is more commonly associated with the former and HSV1 the latter. It is believed that >80% of genital infections are caused by HSV2. Globally, over 500 million people have genital herpes infections and approximately 50 to 80% of the world’s population have oro-labial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1 , can also cause lesions on the fingers (Whitlows) and other areas of the skin.

[0005] The vast majority of HSV infected individuals will not experience any noticeable symptoms. However, some will experience recurrent (and often severe) outbreaks of infection. In the USA, 20 to 40% of the population will get recurrent labial HSV lesions. Significantly, oro-labial cold sores and Whitlows provide a very easy route for transmission of the virus to other individuals which can lead to rarer but much more serious HSV-related pathologies. For example, HSV- related ocular keratitis is a major cause of blindness and HSV can also cause encephalitis in neonates, which is a life-threatening condition. Other disorders believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis and possibly Bell's palsy.

[0006] Primary infection with, or reactivation of an existing herpes virus infection, can be a major cause of disease in immunocompromised individuals. Key at-risk populations include patientsundergoing solid organ or stem cell transplantation, patients undergoing cancer treatment, individuals with HIV / AIDS, and ICU patients.

[0007] Presently, there is no cure for HSV. Medicines have been developed that can to some degree reduce the occurrence and / or shorten the length of outbreaks, but there is a need for improved therapies.

[0008] Currently, nucleoside analogues, such as acyclovir and its prodrugs, e.g., valacyclovir and famciclovir, are used as agents against herpes viruses such as HSV. In order to exert their effects, these nucleoside analogues must be phosphorylated by viral thymidine kinase (TK) and subsequently converted by cellular kinases to the nucleoside triphosphate, which inhibits the activity of the viral DNA polymerase. If the virus has no functionally active TK, as is the case, for example, with resistant HHV1 mutants or with TK-negative viruses, the nucleoside analogues are unable to exert their effects.

[0009] Nucleoside analogues are clinically administered at very high doses, e.g., doses as high as several hundred milligrams to several grams are typically administered per day. Even at these high doses, which are often administered over long treatment durations, these drugs are unable to completely prevent recurrent outbreaks of symptoms from HSV infection. Nucleoside analogues also do little to address the issue of viral shedding, which can asymptomatically facilitate the transmission of HSV to more individuals. Certain nucleoside analogues, particularly when used at high doses, also give rise to safety concerns. For example, since these agents can incorporate into the genome DNA of a host via the host DNA polymerase, their mutagenicity is of concern, as documented for the nucleoside analogue, ganciclovir (Aoki, Chapter 45 in Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases (Eighth Edition) 2015).

[0010] Given the inadequacy of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments.

[0011] One class of compounds currently being investigated are the helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex consisting of helicase, primase, and cofactor subunits, which have functions that are essential for viral DNA replication. These agents are not nucleoside analogues and do not require phosphorylation by TK to inhibit HSV replication and they are therefore potentially active against TK-deficient HSV, which as described above, is a major mechanism of resistance to nucleoside analogues.

[0012] Two examples of helicase-primase inhibitors are BILS-179 BS (Crute et al., (2002) Nature Medicine 8, p. 386-391) and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p. 201-206). Another example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative with the chemical name N-Methyl-N-(4-methyl-5-sulfamoyl-1 ,3-thiazol-2-yl)-2-[4- (pyridin-2-yl)phenyl]acetamide. The compound has been disclosed in WO 2001 / 47904.

[0013] The present disclosure relates to novel methods of synthesizing a certain compound, which is a potent helicase-primase inhibitor. The compound is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]- 4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide and is referred to herein also as ‘Compound T.SUMMARY OF THE DISCLOSURE

[0014] Provided herein are novel synthetic methods to form Compound 1 having the structural formula:

[0015] The synthesis of Compound 1 was first disclosed in International PCT Publication, W02024 / 049760 (Example 22).

[0016] Compound 1 is a potent helicase-primase inhibitor and has an in-vitro EC50 value of approximately 0.019 mM against HSV-1 and 0.011 mM against HSV-2.

[0017] One aspect of the present disclosure is a method of synthesizing Compound 1, or a pharmaceutically acceptable salt thereof, comprising the step of: iv) converting a compound of Formula (IV) to Compound 1 , or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0018] One embodiment of the present disclosure is a method for synthesizing Compound 1, or a pharmaceutically acceptable salt thereof, comprising the steps of: iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0019] One embodiment of the present disclosure is a method for synthesizing Compound 1, or a pharmaceutically acceptable salt thereof, comprising the steps of: ii) converting a compound of Formula (II) to a compound of Formula (III); iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0020] One embodiment of the present disclosure is a method for synthesizing Compound 1 , or a pharmaceutically acceptable salt thereof, comprising the steps of: i) converting Compound 2 to a compound of Formula (II); ii) converting a compound of Formula (II) to a compound of Formula (III); iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0021] In one aspect, there is provided a compound of Formula (II), Formula (III), or Formula(IV), or a salt thereof:wherein X is iodo.

[0022] In one aspect, there is provided the use of one or more of the following compounds in the preparation of Compound 1, or a pharmaceutically acceptable salt thereof:Formula (II) Formula (III) Formula (IV) wherein X is selected from chloro, bromo, iodo, and triflate.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 is an XRPD diffractogram of Form C of Compound 1.

[0024] FIG. 2 shows a DSC thermogram of Form C of Compound 1. The DSC exhibited a sharp endotherm at an onset of 271.7 °C and a peak of 272.4 °C.

[0025] FIG. 3 shows a TGA thermogram of Form C of Compound 1. The TGA data indicated a weight loss of 0.44% up to 200 °C.DETAILED DESCRIPTION OF THE DISCLOSURE

[0026] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0027] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0028] As used herein, “Compound 1” refers to 2-(3-(2',5'-difluoro-[1 ,1'-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2 / - / )-yl)-4-methylthiazole-5-sulfonamide.

[0029] Unless the context requires otherwise, throughout this specification and claims, the words "comprise," "comprising" and the like are to be construed in an open, inclusive sense; the words "a" "an" and the like are to be considered as meaning at least one and are not limited to just one; and the term "about" is to be construed as meaning plus or minus 10%. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.

[0030] When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631 , Angew. Chem. Internet. Ed. Eng. 21 : 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: 657-668) or can be characterized by the manner in which the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (namely, as (+)- or (-)-isomers, respectively). A chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture”.

[0031] In certain cases, depicted substituents may contribute to optical or stereoisomerism. Compounds having the same molecular formula but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers thatare not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers”. A single stereoisomer compound may form one aspect of the present disclosure.

[0032] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0033] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carboncarbon double bond. Substituents around a carbon-carbon double bond are designated as being in the “Z’ or “E” configuration wherein the terms “Z’ and “E’ are used in accordance with IIIPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0034] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0035] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures canalso be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a preexisting one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, C / assics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0036] In some embodiments, the intermediate compounds disclosed herein are provided in a free base or free acid form (parent form). Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the parent compound.

[0037] The intermediate compounds disclosed herein may be provided as salts, for example in a protonated form of the parent compound together with a suitable counter anion. Suitable counter anions include both organic and inorganic anions. Example of suitable inorganic anions include those derived from inorganic acids, including chloride (Cl"), bromide (Br), iodide (I-), sulfate (SO2' ), sulfite (SO32-), nitrate (NOT), nitrite (NC>2'), phosphate (PO '), and phosphite (PO33-). Examples of suitable organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, lactate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, phenylsulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartarate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannic acid and carboxymethyl cellulose. In an embodiment, the counter anion is chloride or formate, such as formate.

[0038] Alternatively, the intermediate compounds disclosed herein may be provided as salts, for example in a deprotonated form of the parent compound together with a suitable counter cation. Suitable counter cations include both organic and inorganic cations. Examples of suitable inorganic cations include alkali metal ions such as Na+and K+, alkaline earth cations such as Ca2+and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include the ammonium ion (i.e. , NF ) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR4+). Examples of substituted ammonium ions include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[0039] The term " pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compoundsincluded in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,1'-methylene-b / s-(2-hydroxy-3-naphthoate)) salts. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0040] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36CI, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0041] Certain isotopically-labeled disclosed compounds {e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated {i.e.,3H) and carbon- 14 i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium {i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0042] In certain embodiments of the present disclosure, the compounds disclosed herein are “stereochemically pure.” A stereochemically pure compound has a level of stereochemical purity that would be recognized as “pure” by those of skill in the art. Of course, this level of purity may be less than 100%. In certain embodiments, “stereochemically pure” designates a compound that is substantially free, i.e. at least about 85% or more, of alternate isomers. In particular embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free of other isomers.

[0043] At various places in the present specification, values may be disclosed in groups or in ranges. It is specifically intended that the description include all individual sub-combination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0044] The use of any and all examples, or exemplary language herein, for example, "such as," "including," or "for example," is intended merely to illustrate better the present teachings and does not pose a limitation on the scope of the disclosure unless claimed.

[0045] The phrase "substantially as shown in figure" refers to an X-ray powder diffraction pattern with at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of its features appearing in the figure.

[0046] The term “relative volume” refers to the volume of a liquid (in mL) used relative to the mass of the limiting starting material (in g). For example, 10 relative volumes of solvent equates to 10 mL for every gram of the limiting starting material.

[0047] The phrase “FIG.” is short for Figure.Methods of Synthesis

[0048] As previously noted, the present disclosure relates to novel synthetic methods for the preparation of Compound 1 .

[0049] W02024 / 049760 provides a method to prepare Compound 1 in Example 22. The Example 22 route is shown in Scheme 1 below.Scheme 1

[0050] The small-scale route shown in Scheme 1 , and further described in Reference Example 1 below, suffers from a number of drawbacks which make it unsuitable for the large-scale manufacture of Compound 1 . Firstly, the Scheme 1 route is not efficient with Compound 1 being synthesized in an overall yield of 9.3% starting from Intermediate 5-1 . Secondly, the route is poorly convergent as intermediate 5A is introduced early in step 2. Thirdly, some of the reagents and solvents used are not suited to large scale manufacture due to either environmental (e.g. dichloromethane) or safety (e.g. phosphorus oxychloride) concerns. Fourthly, steps 1 , 2 and 4 utilise flash column chromatography purification, which is undesirable for large scale manufacture due to time, cost and environmental considerations.

[0051] The inventors have devised a new route described in Scheme 2 below which is suited to the large scale manufacture of Compound 1 as it reduces the burden of impurities, uses higher yielding chemistry and improves the purification scalability.

[0052] A process using the Scheme 2 route is described in Example 2. The Example 2 process avoids the use of chromatography and delivers Compound 1 in a yield of 26% over four synthetic steps starting from Compound 2.Scheme 2Compound 7

[0053] Accordingly, in a first aspect of the disclosure, there is provided a method for synthesizing Compound 1 , or a pharmaceutically acceptable salt thereof, comprising the step of: iv) converting a compound of Formula (IV) to Compound 1 , or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0054] One embodiment of the present disclosure is a method for synthesizing Compound 1 , or a pharmaceutically acceptable salt thereof, comprising the steps of: iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0055] One embodiment of the present disclosure is a method for synthesizing Compound 1 , or a pharmaceutically acceptable salt thereof, comprising the steps of: ii) converting a compound of Formula (II) to a compound of Formula (III); iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0056] One embodiment of the present disclosure is a method for synthesizing Compound 1 , or a pharmaceutically acceptable salt thereof, comprising the steps of: i) converting Compound 2 to a compound of Formula (II); ii) converting a compound of Formula (II) to a compound of Formula (III); iii) converting a compound of Formula (III) to a compound of Formula (IV); and iv) converting a compound of Formula (IV) to Compound 1, or a pharmaceutically acceptable salt thereof,wherein X is selected from chloro, bromo, iodo, and triflate.

[0057] In an embodiment of the method of the first aspect of the disclosure, there is provided an additional step v) of recrystallizing Compound 1. In an embodiment, the recrystallization in step v) gives Form C of Compound 1. Form C is characterized by an XRPD pattern measured using Cu Ka (1 .5406 A) radiation substantially the same as shown in Figure 1 , with peak positions as shown in Table 1.

[0058] In one embodiment, Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20. In one embodiment, Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.2 °20. In one embodiment, Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.1 °20. In one embodiment, Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.1 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.1 °20.Formation of a Compound of Formula (II) - step i)

[0059] As described above, step i) comprises the formation of a compound of Formula (II) from Compound 2.

[0060] In an embodiment, X is selected from bromo and iodo; conveniently X is iodo.

[0061] In an embodiment, the step comprises the reaction of Compound 2 with a compound of Formula (I):Formula (I) wherein Xi and X2 are independently selected from chloro, bromo, iodo, and triflate. In an embodiment, Xi and X2 are independently selected from bromo and iodo. In a convenient embodiment, Xi and X2 are both the same. In a convenient embodiment, Xi and X2 are both bromo. In a most convenient embodiment, Xi and X2 are both iodo. In an embodiment, the compound of Formula (I) is 1 ,4-diiodobenzene.Formation of a Compound of Formula (III) - step ii)

[0062] As described above, step ii) comprises the formation of a compound of Formula (III) from a compound of Formula (II).

[0063] In an embodiment, X is selected from bromo and iodo; conveniently X is iodo.

[0064] In an embodiment, the step comprises the reaction of a compound of Formula (II) with chlorosulfuric acid.Formation of a Compound of Formula (IV) - step iii)

[0065] As described above, step iii) comprises the formation of a compound of Formula (IV) from a compound of Formula (III).

[0066] In an embodiment, step iii) comprises a step iiia), wherein step iiia) comprises the reaction of a compound of Formula (III) with a suitable chlorinating agent to give a compound of Formula (Illa):wherein X is selected from chloro, bromo, iodo, and triflate. In an embodiment, the suitable chlorinating agent is POC or SOCI2, such as POCI3.

[0067] In an embodiment, step iii) comprises a step iiib), wherein step iiib) comprises the reaction of a compound of Formula (Illa) with a suitable aminating agent to give a compound of Formula (IV):Formula (Illa) Formula (IV) wherein X is selected from chloro, bromo, iodo, and triflate. In an embodiment, the suitable aminating agent is ammonia, such as aqueous ammonia.

[0068] In an embodiment, X is selected from bromo and iodo; conveniently X is iodo.Formation of Compound 1 - step iv)

[0069] As described above, step iv) comprises the formation of Compound 1 from a compound of Formula (IV). In an embodiment, X is selected from bromo and iodo; conveniently X is iodo.

[0070] In an embodiment, step iv) step comprises the reaction of a compound of Formula (IV) with a compound of Formula (V):Formula (V) wherein Y is selected from BF3Z and B(OR1)OR2, wherein Z is a suitable counter-cation such as Na or K; R1and R2are hydrogen, Ci-ealkyl, or phenyl; or R1and R2, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester.

[0071] In an embodiment, Y is B(OR1)OR2. In an embodiment, Y is B(OR1)OR2wherein R1and R2are selected from hydrogen, Ci-ealkyl, and phenyl. In a convenient embodiment, Y is B(OH)2. In an embodiment, Y is B(OR1)OR2wherein R1and R2, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester. Suitable 5- to 8- membered cyclic boronic esters include those derived from pinacol, neopentyl glycol, 1 ,3- propanediol, catechol, diethanolamine, / V-methyldiethanolamine, / V-phenyldiethanolamine, and / V-methyliminodiacetic acid (Ml DA).

[0073] In a convenient embodiment X is iodo and Y is B(OH)2.

[0074] Step iv) may be carried out in the presence of a palladium catalyst. Conveniently, step i) comprises reacting a compound of Formula (IV) and a compound of Formula (V) in the presence of a suitable palladium catalyst. Suitable palladium catalysts may be determined by a person skilled in the art and may include Pd(PPhs)4, Pd2(dba)s, Pd(OAc)2, Pd(dppf)Ch, X-Phos-Pd-G3 ((2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 , -biphenyl)[2-(2'-amino-1 ,T- biphenyl)]palladium(ll) methanesulfonate), SPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino-2',6 - dimethoxy-1 , -biphenyl)[2-(2'-amino-1 ,T-biphenyl)]palladium(ll)), cataCXium® A Pd G3 ([(Di(1- adamantyl)-butylphosphine)-2-(2'-amino-1 , -biphenyl)]palladium(ll) methanesulfonate), APhos- Pd-G3 ([4-(Di-terf-butylphosphino)- / \ / , / \ / -dimethylaniline-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate), P(Cys)-Pd-G3 ([(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate), and PEPPSI-IPENT (Dichloro[1 ,3-bis(2,6-Di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)). In an embodiment the palladium catalyst is Pd2(dba)s, Pd(OAc)2, or Pd(dppf)Ch; conveniently, the palladium catalyst is Pd(dppf)Ch.

[0075] In an embodiment, step iv) comprises reacting a compound of Formula (IV) and a compound of Formula (V) in the presence of 0.001 to 0.01 molar equivalents of palladium catalyst, such as 0.003 to 0.007 molar equivalents of palladium catalyst, or about 0.005 molar equivalents of palladium catalyst. In a convenient embodiment, step i) comprises reacting a compound of Formula (I) and a compound of Formula (III) in the presence of 0.001 to 0.01 molar equivalents of Pd(dppf)Ch, such as 0.003 to 0.007 molar equivalents, or about 0.005 molar equivalents of Pd(dppf)CI2.

[0076] In an embodiment, step iv) further comprises reacting a compound of Formula (IV) with a compound of Formula (V) and a base. Suitable bases include sodium carbonate (Na2COs), potassium carbonate (K2CO3), cesium carbonate (CS2CO3), and potassium phosphate (K3PO4); conveniently the base is potassium phosphate (K3PO4).

[0077] Typically, step iv) is carried out in a solvent. Suitable solvents include tetra hydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), isopropyl acetate (IPAc), dimethylformamide (DMF), cyclopentyl methyl ether (CPME), 1 ,2-dimethoxyethane (DME), dimethylacetamide (DMAc), 1 ,4- dioxane, toluene, ethanol, propanol, isopropanol, butan-1-ol, butan-2-ol, pentanol, water, and mixtures thereof. In an embodiment, the solvent is selected from tetrahydrofuran (THF), 2- methyltetrahydrofuran (MeTHF), isopropyl acetate (IPAc), toluene, 1 ,4-dioxane, water, and mixtures thereof. In a convenient embodiment, the solvent is 1 ,4-dioxane, water, or a mixture thereof.

[0078] In a convenient embodiment, step iv) comprises reacting a compound of Formula (IV) and a compound of Formula (V) in the presence of a palladium catalyst, a base, and solvent. In a convenient embodiment, step iv) comprises reacting a compound of Formula (IV) and a compound of Formula (V) in the presence of Pd(dppf)Ch and K3PO4. In a convenient embodiment,step iv) comprises reacting a compound of Formula (IV) and a compound of Formula (V) in the presence of Pd(dppf)Ch and KsPC with 1 ,4-dioxane and water as the solvents.

[0079] Step iv) is typically performed at elevated temperature (above ambient temperature; approximately 20 °C). Methods for providing heat during the reaction are known and include, for example, using a reaction vessel having an external heating jacket or using microwave heating. Step iv) may be carried out at a temperature of from 50 °C to 150 °C, such as 80 °C to 120 °C, or about 85 °C to 95 °C.

[0080] Step iv) may be performed for sufficient time to allow a desired quantity of Compound 1 to form. Typically, step iv) is performed until substantially all of the compound of Formula (IV) has been consumed. Typically, step iv) is carried out for between 6 hour and 40 hours, such as 15 to 35 hours, 20 to 30 hours, or 20 to 25 hours.

[0081] Step iv) may optionally comprise a further step of treating crude Compound 1 with a palladium scavenger to reduce palladium levels in the final material. Suitable scavengers include activated charcoal, trimercaptotriazene (TMT), NaHSCh, sulfur-based functionalized silica, ethylenediamine, 1 ,2-diaminopropane, TMEDA, L-cysteine, and N-acetyl-L-cysteine, such as ethylenediamine. Step iv) may optionally comprise further purification steps, such as recrystallisation, to control the purity and / or physical form of Compound 1 .Recrystallization of Compound 1 - step v)

[0082] As described above, step v) comprises the recrystallization of Compound 1 formed from step iv). In an embodiment, the recrystallization in step v) gives Form C of Compound 1. In one embodiment, step v) gives Form C of Compound 1 and comprises the sub-steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture obtained from step b), optionally for at least 1 hour; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0083] In one embodiment, the first solvent system comprises a solvent wherein Compound 1 has a solubility of at least 25 mg / mL at room temperature, such as at least 50, 75, or 100 mg / mL. Suitably, the first solvent system comprises DMSO, DMF, NMP, or DMAc, most suitably DMSO or DMF. Suitably, the first solvent system comprises DMSO. Suitably, the first solvent system consists essentially of DMSO. Suitably, the first solvent system consists of DMSO. Suitably Compound 1 is dissolved in 1-30 relative volumes of the first solvent system, such as 1-20 relative volumes of the first solvent system, 1-10 relative volumes, 1-5 relative volumes, or 3-8 relativevolumes. Suitably Compound 1 is dissolved in 1-20 relative volumes of DMSO, such as 1-10, 1- 5, 2-4, or 3-8 relative volumes of DMSO.

[0084] Suitably, step a) is performed at 30 to 100 °C. Suitably, step a) is performed at 40 to 100 °C, 50 to 100 °C, or60 to 90 °C, such as 65 to 85 °C, 75 to 85 °C or 70 to 80 °C. In an embodiment, step a) is performed at 30 to 60 °C, such as at 40 to 50 °C.

[0085] Suitably Compound 1 is dissolved in 1-20 relative volumes of DMSO at a temperature of 40 to 100 °C, such as 40 to 50 °C, or 60 to 90 °C (such as 70 to 80 °C).

[0086] Suitably, the second solvent system comprises a solvent wherein Compound 1 has a solubility of less than 50 mg / mL at room temperature, such as less than 20, or less than 10 mg / mL. Suitably, the second solvent system comprises ethanol, methanol, isopropanol, acetone, water, MEK, or benzyl alcohol, most suitably ethanol. Suitably, the second solvent system consists essentially of ethanol. Suitably, the second solvent system consists of ethanol. Suitably 5-40 relative volumes of the second solvent system are added to the solution from step a), such as IQ- 35, 15-35, 5-20, 10-18, or 12-16 relative volumes. Suitably 5-40 relative volumes of ethanol are added to the solution from step a), such as 10-35, 15-35, 5-20, 10-18, or 12-16 relative volumes of ethanol.

[0087] Suitably, the second solvent system is an anti-solvent system.

[0088] Suitably, in step b) the second solvent system is added at 10 to 90 °C, such as at 20 to 90 °C, 30 to 90 °C, 40 to 90 °C, 40 to 80 °C, 55 to 80 °C, or 40 to 70 °C. Suitably, in step b) the second solvent system is added at 50 to 65 °C, such as 50 to 60°C, 55 to 60 °C or 60 °C.

[0089] Suitably, the second solvent system in step b) is added dropwise to the solution from step a).

[0090] Suitably, the addition of the second solvent system in step b) is over a time period of at least 1 hour, such as at least 2 hours, such as at least 5 hours or such as at least 8 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 5 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 7 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 8 hours. Suitably, the addition of the second solvent in step b) is over a time period of 8 to 10 hours.

[0091] Suitably, the addition of the second solvent system in step b) is carried out in two portions. Suitably, 0.5-2 relatives volumes, such as 1-2 relative volumes, of the second solvent system (e.g. ethanol) are added in the first portion and 10-20 relative volumes, such as 10-15 relative volumes, of the second solvent system (e.g. ethanol) are added in the second portion. In an embodiment, 4-8 relatives volumes, such as 5-7 relative volumes, of the second solvent system (e.g. ethanol) are added in the first portion and 20-30 relative volumes, such as 23-29 relative volumes, of the second solvent system (e.g. ethanol) are added in the second portion.Suitably, the first portion of the second solvent system is added over 30 to 60 minutes. In an embodiment, the first portion of the second solvent system is added to the mixture being stirred at 10 to 90 °C, such as 40 to 90 °C, 40 to 80 °C, 40 to 70 °C, 65 to 85 °C, 70 to 80 °C, 50 to 60 °C, or 50 to 55 °C. In an embodiment, the first portion of the second solvent system is added to the mixture being stirred at the same temperature step a) was performed. In an embodiment, the second portion of the second solvent system is added to the mixture being stirred at 10 to 50 °C, or at 50 to 65 °C, such as 55 to 60 °C, 57 to 62 °C, or about 60 °C. Suitably, after the addition of the second solvent system, the mixture is stirred at 57 to 62 °C for 1-2 hours. Suitably, after the addition of the second solvent system, the mixture is stirred at 55 to 60 °C for 1-2 hours.

[0092] In one embodiment, step b) further comprises an additional step (step b2)) of adding a seed of Compound 1 Form C to the solution. Suitably, 0.01 to 10% by weight of the seed relative to the amount of Compound 1 present in the solution in step a) is added. Suitably, 0.1 to 5% by weight of seed is added, such as about 2% by weight. Suitably step b2) is carried out after the first portion of the second solvent system is added to the mixture.

[0093] Suitably, the stirring in step c) is performed at room temperature. Suitably, the stirring in step c) is performed at 18 to 22 °C.

[0094] Suitably, the stirring in step c) is performed for at least 1 hour, such as at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 22 hours, or at least 24 hours. Suitably, the stirring in step c) is performed for at least 1 hour.

[0095] Suitably, step d) comprises isolating the solids by filtration.

[0096] Suitably, step e) comprises drying the solids at a temperature greater than room temperature, such as greater than 30°C, or greater than 40°C. Suitably, step e) comprises drying the solids at a temperature of about 50 °C.

[0097] As described in Example 3, the recrystallization to give Form C may be carried out using DMSO as the solvent (first solvent system) and ethanol as the anti-solvent (second solvent system). Therefore, suitably, the first solvent system comprises DMSO and the second solvent system comprises ethanol. Other solvents and / or anti-solvents may provide improved impurity purging. In an embodiment, the first solvent system comprises DMF, NMP, or DMAc, suitably DMF. In an embodiment, the second solvent system comprises ethanol, methanol, isopropanol, acetone, water, MEK, benzyl alcohol, or a mixture thereof. In an embodiment, the first solvent system comprises DMF, NMP, or DMAc, and the second solvent system comprises ethanol, methanol, isopropanol, acetone, water, MEK, benzyl alcohol, or a mixture thereof. In an embodiment, the first solvent system comprises DMF, and the second solvent system comprises acetone, MEK, benzyl alcohol, or a mixture thereof.

[0098] In an embodiment, there is provided a method of preparing Form C of Compound 1 , wherein the method comprises sub-steps a) to e) of step v) as described above.Intermediates

[0099] In another aspect, the present disclosure relates to intermediates which are useful in the preparation of Compound 1 .

[0100] In one embodiment of this aspect, there is provided a compound of Formula (II), Formula(Ill), or Formula (IV), or a salt thereof:Formula (II) Formula (III) Formula (IV) wherein X is iodo.

[0101] In an embodiment there is provided a compound of Formula (IV), or a salt thereof, wherein X is iodo.

[0102] In an embodiment, there is provided the use of one or more of the following compounds in the preparation of Compound 1 , or a pharmaceutically acceptable salt thereof:Formula (II) Formula (III) Formula (IV) wherein X is selected from chloro, bromo, iodo, and triflate. In an embodiment X is bromo or iodo, such as X is iodo.

[0103] The disclosure is illustrated below by the following non-limiting examples.EXAMPLESAbbreviations

[0104] The following abbreviations are used within this specification:ACN / MeCN: Acetonitrile calcd: calculatedDCM: DichloromethaneDppf: 1 , 1 '-Bis(diphenylphosphino)ferroceneDMEDA: N,N’-dimethylethylenediamineDMSO: Dimethyl sulfoxide eq: EquivalentsEtOAc / EA: Ethyl acetate hr / h: HoursHRMS : High resolution mass spectrometryMTBE: Methyl tert-butyl etherNMR: Nuclear magnetic resonancePd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)TBAB: Tetrabutylammonium bromideTHF: TetrahydrofuranVol / V: Relative VolumeINSTRUMENTATION AND METHODS

[0105] NMR spectra were carried out on Bruker AVANCE NEO 400MHz NMR spectrometer at a temperature of 297-299K. Unless otherwise stated, DMSO-ck was used as the solvent.

[0106] HRMS was carried out using a Vanquish / Orbitrap Exploris 120 LC-MS, with an ESI ion source.Reference Example 1 : Small-scale Synthesis of Compound 1 according to WQ2024 / 049760

[0107] WO2024 / 049760 discloses a method to prepare Compound 1 , as described in Example 22, reproduced below.Step 1 : Synthesis of 1-(4-methylthiazol-2-yl)tetrahvdropyrimidin-2(1 / 7)-one (Intermediate 5-2)

[0108] A mixture of 2-amino-4-methylthiazole (6 g, 52.632 mmol) and 1-chloro-3- isocyanatopropane (6.26 g, 52.632 mmol) in THF (60 mL) was heated at 70 °C for 6 h. To the resulting solution, TBAB (1.7 g, 5.263 mmol) and K2CO3(18.15 g, 131.58 mmol) were added portion wise maintaining the same temperature and stirring continued at 70 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 60-70% EtOAc in heptane) to afford Intermediate 5-2 (5.1 g, 49.2%) as an off-white solid. TLC: 70% EtOAc / heptane (R 0.5). MS calcd. for Chemical Formula: C8HH N3OS: 197.06; Found: 198.17 [M + 1]+.1H NMR (400 MHz, DMSO-d6) 5 7.30 (s, 1 H), 6.60 (s, 1 H), 3.99 (t, J = 5.4 Hz, 2H), 3.20 - 3.19 (m, 2H), 2.28 (s, 3H), 1.99 - 1.89 (m, 2H).Step 2: Synthesis of 1-(2',5'-difluoro- biphenyl1-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1 / 7)-one (Intermediate 5-3)

[0109] To a stirred solution of Intermediate 5-2 (5 g, 25.380 mmol) in 1 ,4-dioxane (100 mL) were added Intermediate 5A (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol) followed by Cui (0.96 g, 5.076 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture, 1 ,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 120 °C for 24 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through Celite bed and washed with ethyl acetate. The filtrate was diluted with water and, extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluting with 30-40% EtOAc in heptane) to afford Intermediate 5-3 (4.1 g, 41.9%) as an off-white solid. TLC: 50% EtOAc / Heptane (Rf: 0.5). MS calcd. for Chemical Formula: C20H17F2N3OS: 385.11 ; Found: 385.90 [M + 1]+.1H NMR (400 MHz, DMSO-d6) 5 7.61 (d, J = 7.8 Hz, 2H), 7.54 - 7.35 (m, 4H), 7.35 - 7.21 (m, 1 H), 6.70 (s, 1 H), 4.17 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 4.9 Hz, 2H), 2.26 (s, 3H), 2.24 - 2.21 (m, 2H).Step 3: Synthesis of 2-(3-(2',5'-difluoro- biphenyl1-4-yl)-2-oxotetrahvdropyrimidin-1(2 / 7)-yl)-4-methylthiazole-5-sulfonic acid (Intermediate 5-4)

[0110] To a stirred solution of Intermediate 5-3 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0 °C in an inert atmosphere, chlorosulfuric acid (2.07 mL, 31.168 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to afford Intermediate 5-4 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R 0.2). MS calcd. for Chemical Formula: C20H17F2N3O4S2: 465.06; Found: 466 [M + 1]+.Step 4: Synthesis of 2-(3-(2',5'-difluoro- biphenyl1-4-yl)-2-oxotetrahydropyrimidin-1 (2 / - / )-yl)-4-methylthiazole- 5-sulfonamide (Compound 1)

[0111] A stirred solution of Intermediate 5-4 (3.3 g, 7.096 mmol) in POCI3 (33 mL) was allowed to stir at 90 °C for 5 h. The reaction mixture was concentrated under reduced pressure to dryness. The resulting residue obtained was dissolved in THF (66 mL), and aqueous ammonia (33 mL)was added at -5 °C and stirring continued at room temperature for another 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 100% EtOAc) to afford the desired product Compound 1 (1.1 g, 44.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 7.65-7.59 (m, 2H), 7.55 (br s, 2H), 7.53-7.48 (m, 2H), 7.48-7.36 (m, 2H), 7.31-7.25 (m, 1 H), 4.17 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.29-2.18 (m, 2H).

[0112] A typical batch of Compound 1 prepared according to the synthetic route described in Reference Example 1 contained thirteen separate impurities greater than or equal to the limit of quantification (0.05% by HPLC), with the total impurity content being 1.71%.Example 2: Improved Large-scale Synthesis of Compound 1THF, 65 °CCompound 2Cui, DMEDA, K2CO31 ,4-dioxane, 100 °CCompound 3Step 1 : Formation of Compound 2THF, 65 °CCompound 2

[0113] Stage 1 : THF (12 V, 216 L), 2-amino-4-methylthiazole (1.0 eq., 18 kg), and 1-chloro-3- isocyanatopropane (1.2 eq., 22.5 kg) were charged into a reactor under nitrogen atmosphere, and swapped with nitrogen 3 times. The mixture was heated to 60-70 °C, and stirred for 4 h. The mixture was cooled to 20-30 °C and TBAB (0.1 eq., 5.04 kg) was added followed by potassium carbonate (2.5 eq., 54.5 kg) added portion wise. The reactor was swapped with nitrogen 3 times and the mixture was refluxed at 70 °C for 16 hr. After the reaction was complete, the mixture was cooled to ambient temperature, filtered, and the cake was washed with THF (2 V). The filtrate was concentrated to 1.5-3 V and diluted with EtOAc (5 V). This mixture was concentrated to 1.5- 2 V, diluted with EtOAc (1 V) and then stirred at 45-55 °C for 4-5 hr. After cooling to 5-15 °C over 4-5 hr, the suspension was filtered and the cake was washed with EtOAc (2 V) and dried at 40- 50 °C to give Compound 2 (14.95 kg; 51.2% yield).1H NMR (DMSO-d6, 400 MHz) 8 7.33 (s, 1 H), 6.60 (d, 1 H), 3.98 (t, 2H), 3.24-3.16 (m, 2H), 2.22 (d, 3H), 1.93 (quin, 2H). HRMS (ESI) m / z calculated for C8HnN3OS ([M+H]+) 198.0696, found 198.0691.Step 2: Formation of Compound 4Cui, DMEDA, K2CO3Compound 2 1 ,4-dioxane Compound 4100 °C

[0114] Dioxane (20 V, 305 kg), Compound 2 (1.0 eq., 14.75 kg), Compound 3 (1.1 eq., 27.14 kg), potassium carbonate (2.5 eq., 25.8 kg), and DMEDA (0.4 eq., 2.64 kg) were charged into a first reactor in sequence under nitrogen atmosphere, and swapped with nitrogen 3 times. Cui (0.2 eq., 2.85 kg) was charged to the reactor under nitrogen atmosphere, and swapped with nitrogen 3 times. The mixture was refluxed at 95-105 °C over approx. 30 h. After the reaction was complete, the mixture was cooled to 15 °C, filtered through Celite® (1.0 x) and the cake was washed with THF (2-3 V). The filtrate was concentrated to 1.5-3V and diluted with MTBE (5 V). This mixture was concentrated to 1-2 V, diluted with MTBE (2-3 V) and then stirred at 15-25 °C for 8-10 hr. The mixture was then filtered, and the cake was washed with MTBE (1-2 V) and dried at 40-50 °C to give crude product.

[0115] In a second reactor the crude product in EtOAc (25 V) was stirred at 45-55 °C for 10-12 hr, then filtered through Celite® (1.0 x) and the filtrate was washed with 25 wt% aq. NH3(5 V X2), brine (5 V X 2), and water (5 V x 2). The organic phases were concentrated to 1-2 V, and MTBE (2-3V) was charged to the reactor and the mixture was stirred at 20-30 °C for 6-8 hr. The mixture was then filtered, and the cake was washed with MTBE (1 V) and dried at 40-50 °C to give Compound 4 (12.7 kg; 42.5% yield).1H NMR (DMSO-d6, 400 MHz) d 7.77-7.70 (m, 2H), 7.23-7.16 (m, 2H), 6.69 (d, 1 H), 4.14 (t, 2H), 3.73 (t, 2H), 2.25 (d, 3H), 2.18 (quin, 2H). HRMS (ESI) m / z calculated for CI4HI4IN3OS ([M+H]+) 399.9975, found 399.9971.Step 3: Formation of Compound 5

[0116] Acetonitrile (10 V, 124 L), and Compound 4 (1.0 eq., 12.4 kg), were charged into a reactor under nitrogen atmosphere, and swapped with nitrogen 3 times. The reactor was cooled to 0-10 °C and chlorosulfuric acid (3.0 eq., 10.86 kg) was added. The mixture was stirred at 15- 25 °C for 30-40 h. After the reaction was complete, the mixture was filtered, and the cake was washed with MeCN (1-2 V) and dried at 40-50 °C to give Compound 5 (13.3 kg; 89.3% yield).1H NMR (DMSO-d6, 400 MHz) d 7.78-7.70 (m, 2H), 7.23-7.16 (m, 2H), 4.09 (t, 2H), 3.73 (t, 2H), 2.33 (s, 3H), 2.17 (quin, 2H). HRMS (ESI) m / z calculated for CI4HI4IN3O4S2([M+H]+) 479.9543, found 479.9539.Step 4: Formation of Compound 6

[0117] Stage 1 : Compound 5 (1.0 eq., 6.50 kg) and POCI3 (10 V, 109 kg) were heated at 95- 105 °C for 40-50 h in a first reactor. MeCN (5 V) was added to the reactor and the mixture was concentrated to 1.5-2 V at 50-60 °C. This MeCN addition / concentration procedure was repeated three further times. THF (10 V) was the added to the reactor to form a suspension.

[0118] Stage 2: In a second reactor THF (10 V) was cooled to 0-10 °C. 25 wt% ammonia in water (10 V, 59.4 kg) was added to the second reactor, followed by addition of the suspension from the first reactor maintaining the temperature at 0-15 °C. The mixture was then stirred at 15- 25 °C for 12 h. After the reaction was complete, the mixture was charged into a separate reactor containing THF (250 V) and EA (50 V). The mixture was washed with brine (50 V), and 1 :1 25wt% aq. NH3 : brine (100 V x 3). The organic phase was concentrated to 10-15 V, diluted with THF (5 V), and the slurry was stirred at 15-25 °C for 4-5 h, filtered and the cake was washed with THF (1 V) and dried to give Compound 6 (5.27 kg; 81 % yield).1H NMR (DMSO-d6, 400 MHz) 8 7.79-7.72 (m, 2H), 7.57 (s, 2H), 7.24-7.18 (m, 2H), 4.13 (t, 2H), 3.74 (t, 2H), 2.44 (s, 3H), 2.19 (quin, 2H). HRMS (ESI) m / z calculated for C14H15IN4O3S2 ([M+H]+) 478.9703, found 478.9698.Step 5: Formation of Compound 1

[0119] Compound 6 (1.0 eq. 5.22 kg), Compound 7 (1.5 eq., 2.58 kg), dioxane (30 V), water (15 V) and K3PO4 (3.0 eq., 6.94 kg) were charged to a reactor in sequence under nitrogen atmosphere. The atmosphere was swapped with nitrogen 3 times. Pd(dppf)Cl2 (0.005 eq., 40 g) was charged to the reactor, and the atmosphere was swapped with nitrogen 3 times. The mixture was stirred at 85-95 °C for 20 h. After the reaction was complete, the mixture was cooled and charged into a separate reactor containing THF (300 V) and EA (100 V). The mixture was washed with brine (50 V), 3:5 aq. L-cysteine solution (5%): brine (80 V x 3), and the organic phase was stirred with active carbon (0.3 X) (ZX-777) at 45-55 °C for 10-12 h (x 3). The mixture was then filtered, the cake washed with THF (1 V) and the filtrate concentrated to 10-15 V. THF (5 V) was added and the mixture stirred for 4 h at 20-30 °C. The slurry was filtered, and the cake was washed with THF (1-2 V), and dried to obtain Compound 1 (4.25 kg; 84% yield). Purity by HPLC = 99.35%.1H NMR (DMSO-d6, 400 MHz) 8 7.64-7.62 (m, 2H), 7.57 (s, 2H), 7.53-7.7.52 (m, 2H), 7.5-7.4 (m, 2H), 7.3-7.2 (m, 1 H), 4.17 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=5.6 Hz), 2.46 (s, 3H), 2.26- 2.21 (m, 2H). HRMS (ESI) m / z calculated for C20H19F2N4O3S2 ([M+H]+) 465.0861 , found 465.0865.Example 3: Recrystallization of Compound 1

[0120] Crude Compound 1 (~7 kg) was stirred in DMSO (3.5 relative volumes) at 70-80 °C in a first reactor to form a solution. The solution was then filtered through a 0.2 pm filter into a second pre-warmed (70 to 80 °C) reactor, the first reactor being subsequently rinsed with DMSO (0.5 relative volumes) and the rinse being transferred to the second reactor. The mixture was stirred at 70-80 °C until clear. Ethanol (1 rel. vol.) was then added slowly over a period of 30-60 minutes whilst maintaining the batch temperature at 70-80 °C. The internal batch temperature was decreased to 55 to 60 °C (cooling rate 8-12 °C per hour), crystal seed (2 wt%) was added to the reactor, and the mixture was stirred at 55-60 °C for 2-3 hours. Ethanol (15 rel. vol.) was thenadded slowly over a period of 8-10 hr. The contents were stirred at 55 to 60 °C for 1 to 2 hours and then cooled at a cooling rate of 3-7 °C per hour to give a final batch temperature of 18-22 °C. The mixture was stirred at 18-22 °C for 12-24 hours and was then filtered (isolated via centrifugation), washed with ethanol (2 x 4 volumes) and the cake dried at 45 to 55 °C for 12-24 hr to give ~7 kg of Compound 1 Form C as an off white to light yellow solid with a purity by HPLC of 99.8%.

[0121] The crystalline form obtained had an XRPD diffractogram as shown in Figure 1 and was designated as Form C. Peak positions present in the XRPD diffractogram acquired for Form C are presented in Table 1. DSC shows a sharp melting endothermic event with an onset temperature of 271.7 °C (see Figure 2), while TGA shows a weight loss of 0.44% up to 200 °C (see Figure 3). Form C was determined to be an anhydrous crystalline form of Compound 1.Table 1 - XRPD peak positions for Form C

[0122] All publications, patents and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used.

[0123] Although specific embodiments of the present disclosure are herein illustrated and described in detail, the disclosure is not limited thereto. The above detailed descriptions are provided as exemplary of the present disclosure and should not be construed as constituting any limitation of the disclosure. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the disclosure are intended to be included with the scope of the appended claims.

[0124] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS1. A method of synthesizing Compound 1, or a pharmaceutically acceptable salt thereof, comprising a step of converting a compound of Formula (IV) to Compound 1 , or a pharmaceutically acceptable salt thereof:wherein X is selected from chloro, bromo, iodo, and triflate.

2. The method according to claim 1 , wherein the step comprises the reaction of a compound of Formula (IV) with a compound of Formula (V):Formula (V) wherein Y is selected from BF3Z and B(OR1)OR2, wherein Z is a suitable counter-cation such as Na or K; R1and R2are hydrogen, Ci-ealkyl, or phenyl; or R1and R2, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester.

3. The method according to claim 3, wherein Y is B(OR1)OR2, such as Y is B(OH)2.

4. The method according to any one of claims 1 to 3, further comprising a step of converting a compound of Formula (III) to a compound of Formula (IV):Formula (III) Formula (IV) wherein X is selected from chloro, bromo, iodo, and triflate.

5. The method according to claim 4, further comprising a step of converting a compound ofFormula (II) to a compound of Formula (III):Formula (II) Formula (III) wherein X is selected from chloro, bromo, iodo, and triflate.

6. The method according to claim 5, further comprising a step of converting Compound 2 to a compound of Formula (II):Compound 2 Formula (II) wherein X is selected from chloro, bromo, iodo, and triflate.

7. The method according to claim 6, wherein the step comprises the reaction of Compound 2 with a compound of Formula (I):Formula (I) wherein Xi and X2 are independently selected from chloro, bromo, iodo, and triflate.

8. The method according to claim 7, wherein Xi and X2 are both the same, such as Xi and X2 are both iodo.

9. The method according to any one of claims 1 to 6, wherein X is bromo or iodo.

10. The method according to claim 9, wherein X is iodo.

11. The method according to any one of claims 1 to 10, wherein the method comprises a step of recrystallizing Compound 1.

12. The method according to claim 11 , wherein the recrystallization provides a crystalline form characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiationcomprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20, and optionally one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.2 °20.

13. The method according to claim 11 or 12, wherein the recrystallization step comprises the sub-steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture obtained from step b), optionally for at least 1 hour; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

14. A compound of Formula (II), Formula (III), or Formula (IV), or a salt thereof:Formula (II) Formula (III) Formula (IV) wherein X is iodo.

15. Use of one or more of the following compounds in the preparation of Compound 1 , or a pharmaceutically acceptable salt thereof:wherein X is selected from chloro, bromo, iodo, and triflate.

16. Use according to claim 15, wherein X is bromo or iodo, such as X is iodo.

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