Cyclic urea thiazolyl compounds for the treatment of HSV

Abstract

The present disclosure provides, in part, cyclic urea thiazolyl compounds, and pharmaceutical compositions thereof, and methods for treating and preventing HSV infection. In one embodiment, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 401,877, filed August 29, 2022, U.S. Provisional Application No. 63 / 445,427, filed February 14, 2023, and U.S. Provisional Application No. 63 / 472,494, filed June 12, 2023, the contents of which are incorporated herein by reference. [Background technology]

[0002] Human herpesviruses are large, enveloped, double-stranded DNA viruses that share the common characteristic of establishing lifelong infections in humans. This is achieved through their ability to persist in the host either as a dormant, symptomless latent infection or as a lytic infection with associated symptoms after activation. These viral infections are widespread worldwide, and it is notable that over 90% of all humans are chronically infected with multiple human herpesviruses.

[0003] Human herpesviruses are classified into three subfamilies (i.e., α, β, and γ) based on their biological properties, and the family consists of eight members: herpes simplex virus subtypes 1 and 2 (HSV1, HSV2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesviruses 6 to 8 (HHV6 to 8).

[0004] HSV1 and 2 infections can cause disease in immunocompetent individuals. Both subtypes cause cutaneous genital / anal and labial / nasal (herpes simplex) lesions, but HSV2 is more commonly associated with the former, while the latter is associated with HSV1, so it is believed that over 80% of genital infections are caused by HSV2. Worldwide, over 500 million people suffer from genital herpes infections. Symptoms vary but are typically most severe upon initial infection and can last for weeks to months. Approximately 50-80% of the world's population is infected with labial HSV, which is the primary cause of herpes simplex. HSV, especially HSV1, can also cause lesions on the fingers (whitlow) and other areas of the skin.

[0005] The majority of people infected with HSV experience no noticeable symptoms. However, some experience recurrent outbreaks of infection. In the United States, 20-40% of the population has recurrent HSV lip lesions. Importantly, cold sores and whitlow provide a very easy route for the virus to spread to other individuals, which can lead to rarer but much more serious HSV-related conditions. For example, HSV-related ocular keratitis is a leading cause of blindness. HSV can also cause neonatal encephalitis, a life-threatening condition. Other diseases thought to be caused by HSV include herpes gladiatorum, Moller's meningitis, and possibly Bell's palsy.

[0006] Primary infection or reactivation of a pre-existing herpesvirus infection can be a major cause of disease in immunocompromised individuals. Immunocompromised populations at major risk include patients undergoing solid organ or stem cell transplants, HIV / AIDS patients, and ICU patients.

[0007] Currently, there is no cure for HSV. Although medications have been developed that can prevent or shorten outbreaks to some extent, improved therapies are needed to treat HSV infection and inhibit viral replication.

[0008] Currently, nucleoside analogs such as acyclovir and its prodrugs, e.g., valacyclovir and famciclovir, are used as drugs against herpes viruses such as HSV. To exert their effects, these nucleoside analogs must first be phosphorylated by viral thymidine kinase (TK) and then converted by cellular kinases to nucleoside triphosphates that inhibit the activity of viral DNA polymerase. If the virus does not have a functionally active TK, such as in the case of resistant HHV1 mutants or TK-negative viruses, the active substance cannot exert its effect.

[0009] Nucleoside analogs are clinically administered at high doses, ranging from hundreds of milligrams to several grams per day, and even higher doses, and over long periods of treatment, these compounds do not completely prevent the recurrence of symptoms from HSV infection. High doses also result in increased levels of adverse effects.

[0010] Viral shedding is also common in HSV patients and may asymptomatically facilitate the transmission of HSV to a larger number of individuals. Nucleoside analogs have done little to address this; for example, long-term suppressive treatment with valacyclovir has been shown to reduce transmission risk by only 46%. Because nucleoside analogs can be incorporated into the host's genomic DNA via host DNA polymerases, the mutagenic potential of these drugs is also a concern, as has been documented for the nucleoside analog, ganciclovir.

[0011] Given the inadequacies of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments.

[0012] One class of compounds being investigated for the treatment of HSV is helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action against HSV types 1 and 2. They inhibit the viral heterotrimeric complex, which consists of helicase, primase, and cofactor subunits, essential for viral DNA replication. They are not nucleoside analogs and do not require phosphorylation by TK to inhibit HSV replication. Therefore, as noted above, they are potentially active against TK-deficient HSV, a major mechanism of resistance to nucleoside analogs such as acyclovir.

[0013] Two examples of helicase-primase inhibitors are BILS-179BS and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p201-206). BILS-179BS was administered orally, but early clinical trials were discontinued due to adverse events. An example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative with the chemical name N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide. This compound is disclosed in WO 2000 / 53591. WO 2001 / 047904 discloses thiazolylamide derivatives and their use as antiviral agents. WO 2000 / 053591 discloses thiazolyl derivatives and their use as antiviral agents. WO 2017 / 174640 discloses aminothiazole derivatives useful as antiviral agents. WO 2019 / 068817 discloses enantiomers of substituted thiazoles as antiviral compounds. There remains a need for additional antiviral compounds for the treatment and prevention of HSV infections that have improved profiles with respect to safety, efficacy, selectivity and / or bioavailability. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] International Publication No. 2000 / 053591 [Patent Document 2] International Publication No. 2001 / 047904 [Patent Document 3] International Publication No. 2017 / 174640 [Patent Document 4] International Publication No. 2019 / 068817 [Non-patent literature]

[0015] [Non-Patent Document 1] Katsumata et al.(2018)Biochem Pharm 158 p201-206 Summary of the Invention

[0016] In one embodiment, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0017] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0020] In another aspect, the present invention provides a compound of formula II [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0021] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0022] In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION

[0024] The FDA-approved nucleoside drug, acyclovir, and its prodrug, valacyclovir, have been the mainstay of HSV treatment for many years. There has been no regulatory approval of a small molecule drug to treat HSV in over 20 years, representing an area of ​​significant unmet medical need.

[0025] Pritelivir has entered Phase III clinical development by AiCuris for the treatment of HSV. Bayer has filed two scaffold patent applications related to pritelivir. The first application, WO2000 / 53591 (filed February 24, 2000), relates to compounds with an acyclic urea core. The second application, WO2001 / 047904 (filed December 12, 2000), relates to compounds containing pritelivir with an acyclic amide core. The discovery of pritelivir (BAY 57-1293) is reviewed in G. Kleymann, "Discovery, SAR and Medicinal Chemistry of Herpesvirus Helicase Primase Inhibitors," Curr. Med. Chem. - Anti-Infective Agents, 2004, 3, 69-83.

[0026] Of the 227 exemplary acyclic urea compounds disclosed in WO2000 / 53591, in vitro HSV-1 and HSV-2 biological assay data are provided for only four examples: 43, 123, 94, and 2. The structures of examples 123 and 152 are shown below. [ka]

[0027] Similarly, of the 132 exemplary acyclic amide compounds in WO2001 / 047904, in vitro HSV-1 and HSV-2 biological assay data is provided for only seven examples: 14, 57, 8, 23, 38, 87, and 126. The structures of examples 87 and 38 are shown below. [ka]

[0028] Example 5 described herein is a preferred compound of the present invention. It has an aqueous solubility at about pH 7.0 (measured at room temperature) of less than 5 μg / ml. Animal studies were conducted to determine the half-life and clearance of Example 5. Intravenous administration of a solution of the compound to rats, dogs, monkeys, and minipigs at doses of 0.2 mg / kg, 0.15 mg / kg, 0.2 mg / kg, and 0.25 mg / kg, respectively, resulted in the terminal half-lives and clearances shown in the table below. [Table 4]

[0029] Based on the above pharmacokinetic data in multiple species and using allometric scaling, the predicted human biological terminal half-life of the compound is 7.6 days (182 hours) with a clearance of 0.06 L / hour.

[0030] Table 1 shows comparative biological assay data for Example 5 of the present invention with the four prior art compounds shown above that either lack a substituent on the urea nitrogen atom between the carbonyl and phenyl moieties (acyclic urea) or lack a substituent on the carbon atom between the carbonyl and phenyl moieties (acyclic amide). The prior art compounds were prepared according to known procedures, and all biological assay data presented in Table 1 were obtained using the biological assays described herein. [Table 1]

[0031] The cyclic urea compounds of the present invention incorporate two novel structural changes not present in these prior art compounds. First, both nitrogen atoms have covalent bonds to carbon atoms, making them tetrasubstituted ureas. Second, the N-alkyl groups attached to the nitrogen atoms are linked to form a ring. These features are not taught or suggested in the above-mentioned Bayer patents.

[0032] Only one acyclic urea compound, Example 38 of WO 2000 / 53591, features a tetrasubstituted core ring (i.e., a core ring with substituents attached to both urea nitrogen atoms). More specifically, all exemplified compounds are substituted with a diverse set of substituents on the nitrogen bearing the thiazole heterocycle, but only Example 38 is further substituted on the opposite urea nitrogen atom. Similarly, only one compound, Example 45 of WO 2001 / 047904, has a substituent on the benzyl carbon atom next to the amide carbonyl, but there is a diverse set of substituents on the amide nitrogen. [ka]

[0033] No biological data is provided for any of these compounds, and there is no teaching, suggestion, or motivation for cyclizing the urea moiety in WO 2000 / 53591 or WO 2001 / 047904. Nevertheless, applicants have discovered that the novel cyclic urea compounds described herein, particularly tetrahydropyrimidin-2(1H)-ones, are surprisingly active and have distinct physical and biological properties compared to their acyclic counterparts.

[0034] Since no biological data was provided in the prior art for the above Examples 38 and 45, Applicant prepared a novel acyclic tetrasubstituted urea Reference Compound A for direct comparison of biological activity to Example 5. Applicant notes that direct comparison with Example 38 of WO2000 / 53591 may yield ambiguous results due to the presence of a methyl ester moiety on the terminal phenyl group. [ka]

[0035] As shown in Table 2, Reference Compound A is 44-fold less active in the HSV-1 assay than Example 5 and 92-fold less active in the HSV-2 assay than Example 5. Applicants also note that compared to the acyclic amide analog Example 87 shown above, Reference Compound A is 50-fold less active in the HSV-1 assay and 54-fold less active in the HSV-2 assay. [Table 2]

[0036] Without the specific teachings of the prior art, it would have been impossible to predict in advance the effect on activity of alkylation of the urea nitrogen atom between the urea carbonyl and the phenyl group, as in Reference Compound A. The comparative data presented above demonstrate a substantial decrease in the biological activity of acyclic tetrasubstituted ureas. Without structural information showing how the compound binds to its target, it is impossible to know why methylation reduces activity. There are several hypotheses that may explain this observation. Without being bound by theory, these include the following: 1) If the urea NH forms an H-bond to the target, methylation removes the H-bond donating the NH, 2) there may not be enough space on the target to accommodate the methyl group, 3) if the urea carbonyl forms an H-bond to the target, methylation may sterically interfere with and weaken the interaction, 4) methylation may alter the conformational dynamics of the urea, limiting its ability to form a favorable binding conformation, 5) methylation alters the physical properties of the molecule that may reduce its propensity to partition into the inhibitor binding pocket, and 6) methylation alters the physical properties of the molecule that may reduce its ability to enter cells or access the target once inside the cell. Thus, the behavior observed in Example 5, where cyclization of the urea moiety significantly increases biological activity, can be considered unexpected and surprising from a medicinal chemistry perspective.

[0037] Applicant further points out that, generally in medicinal chemistry, cyclization of acyclic moieties results in reduced activity because rotational degrees of freedom are limited to one conformer, which is statistically unlikely to be a favorable confirmation at the binding site. Without being bound by theory, additional possible explanations for the surprising results presented herein include, but are not limited to, the following:

[0038] 1. Conformational Preference: Cyclization of compound 5 can result in a specific conformation that more favorably aligns with the target binding site, allowing for stronger interactions and increased biological activity. This preferred conformation can enhance binding affinity and efficacy.

[0039] 2. Structural Rigidity: The cyclized form of compound 5 may exhibit greater structural rigidity, resulting in improved stability and a reduced entropic cost of binding, which may promote more optimal binding geometries and improve target binding.

[0040] 3. Spatial constraint: Cyclization allows the compound to adopt a three-dimensional shape that complements the binding pocket of the target, which may result in improved molecular recognition and enhanced biological activity.

[0041] Applicants have further discovered that in the novel cyclic ureas of the present invention, the six-membered core ring (i.e., tetrahydro-2(1H)-pyrimidinones) is generally more active than the corresponding five-membered core ring (i.e., 2-imidazolidinones). Consider the following two sets of compounds: Example 5 / 104 and Example 259 / 324, which have the following structures: [ka]

[0042] As shown in Table 3, Example 5 is 91-fold more active than Example 104 (a five-membered ring analog) in the HSV-1 assay and over 200-fold more active in the HSV-2 assay. Similarly, Example 259 is 4-fold more active than Example 314 (a five-membered ring analog). [Table 3]

[0043] The specific reasons behind this trend are unclear and will require detailed analysis of the compound's interactions with the target, including potential differences in conformational flexibility, binding affinity, and steric effects. Without being bound by theory, the larger size of the six-membered core ring may contribute to improved binding interactions and increased potency compared to the five-membered core ring, which may be the result of increased conformational space accessible to the six-membered ring.

[0044] The features and other details of the present disclosure will now be more particularly described. Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims are summarized here. These definitions should be read in light of the remainder of the disclosure and as understood by those skilled in the art. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0045] definition As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include those described herein as C 1-6 Alkyl and C 1-4 These include, but are not limited to, straight or branched chain hydrocarbons of 1 to 6 or 1 to 4 carbon atoms, referred to as alkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0046] As used herein, the term "alkylene" refers to a biradical alkyl group.

[0047] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include those described herein as C 2-6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkenyl, including, but not limited to, vinyl, allyl, butenyl, and pentenyl.

[0048] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include those described herein as C 2-6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkynyl, including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0049] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include those described herein as C, C, C-, C-C ... 1-6 Alkoxy and C 1-4 Examples of alkoxy groups of 1 to 6 or 1 to 4 carbon atoms, referred to as alkoxy, include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0050] The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with an alkoxy group. Exemplary alkoxyalkyl groups include, but are not limited to, C 1-3 Alkoxy C 1-6 Alkyl and C 1-4 Alkoxy C 1-6 C, called alkyl1-3 Alkoxy group or C 1-4 Alkoxy-substituted C 1-6 Examples include, but are not limited to, alkyl groups. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0051] As used herein, the term "cyano" refers to CN.

[0052] As used herein, the term "monocycloalkyl" refers to, for example, C 3-6 It refers to saturated monocyclic hydrocarbon groups of 3 to 6 carbons, referred to as monocycloalkyl. Examples include, but are not limited to, cyclooctyl, cycloheptyl, cyclohexyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

[0053] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0054] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups include those described herein as haloC 1-6 Alkyl and HaloC 1-4 C substituted with one or more halo groups, referred to as alkyl 1-6 Alkyl or C 1-4 Examples of alkyl include, but are not limited to, haloC 1-6 Alkyl refers to a straight or branched alkyl group of 1 to 6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CHF, -CHCl, -CHF, -CF, CFCH-, CHCF-, CFCCl-, and CFCF-.

[0055] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Exemplary alkoxy groups include those described herein as haloC 1-6 Alkoxy and HaloC 1-4 C substituted with one or more halo groups, referred to as alkoxy 1-6 Alkoxy or C 1-4 Examples include, but are not limited to, alkoxy. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O-CF3CH2O-, and CF3CF2O-.

[0056] As used herein, the terms "hydroxy" and "hydroxyl" refer to OH.

[0057] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxy C 1-6 Alkyl and hydroxy C 1-4 C substituted with one or more hydroxy groups, called alkyl 1-6 Alkyl or C 1-4 Examples include, but are not limited to, alkyl. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, (CH3)2C(OH)CH2-, and HOCH2CH(OH)CH2-.

[0058] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups. Exemplary hydroxyalkoxy groups include those described herein as hydroxy C 1-6 Alkoxy and Hydroxy C 1-4 C substituted with one or more hydroxy groups, called alkoxy 1-6 Alkoxy or C 1-4Examples include, but are not limited to, alkoxy. Examples include, but are not limited to, HOCHO-, HOCHCHO-, CHCH(OH)CHO-, (CH)C(OH)CHO-, and HOCHCH(OH)CHO-.

[0059] As used herein, "R n R m The term "N-alkyl-" refers to an N-alkyl group, as defined herein. n R m This refers to an alkyl group substituted with an N-group. n R m As N-alkyl-groups, R n R m NC 1-6 Alkyl and R n R m NC 1-4 One or more R n R m C substituted with N-group 1-6 Alkyl or C 1-4 Examples include, but are not limited to, alkyl, NHCH—, NH(CH)CH—, N(CH)CHCH—, and CHCH(NH)CH—.

[0060] As used herein, "R n R m The term "N-alkoxy" refers to any group of R n R m Refers to an alkoxy group substituted with an N-group. Representative R n R m As used herein, the N-alkoxy groups are each represented by R n R m NC 1-6 Alkoxy and R n R m NC 1-4 One or more R n R m C substituted with N-group 1-6 Alkoxy or C 1-4Examples include, but are not limited to, alkoxy. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0061] As used herein, a bicyclic ring refers to, for example, [ka] When shown as having a floating attachment point and / or floating substituents, such as, bicyclic rings can be attached through a carbon atom on either ring, and the substituents (e.g., R 33 It means that the group(s) can be independently attached to either or both rings.

[0062] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, livestock animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated with the methods of the present disclosure is preferably a mammal in which treatment of an HSV infection is desired.

[0063] "Modulation" includes antagonism (eg, inhibition), agonism, partial antagonism and / or partial agonism.

[0064] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0065] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0066] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0067] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. The compounds included in the compositions of the present invention are basic in nature and are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts with 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-bis(2-hydroxy-3-naphthoate)). The compounds contained in the present compositions are acidic in nature and can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present compositions that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0068] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of the compound that will elicit the biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect.

[0069] The term "treating" includes any effect such as alleviating, reducing, modulating, or eliminating a viral infection that results in amelioration of the disease.

[0070] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term "stereoisomer" consists 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, although those of skill in the art will recognize that the structure may implicitly represent chiral centers. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, although those of skill in the art will recognize that the structure may implicitly represent chiral centers.

[0071] The compounds of the present disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. [ka] indicates a bond, which may be a single bond, double bond, or triple bond, as described herein. Substituents around a carbon-carbon double bond are designated to be in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be designated as "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond.

[0072] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings 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 is designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," with the term "cis" referring to substituents on the same side of the plane of the ring and the term "trans" referring to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring are designated "cis / trans."

[0073] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary and separating the resulting diastereomeric mixture by recrystallization or chromatography, followed by liberation of the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also 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, i.e., chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, are well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0074] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0075] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those enumerated 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 normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0076] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H), and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those disclosed in the examples herein by substituting a non-isotopically labeled reagent for an isotopically labeled reagent.

[0077] The term "prodrug" refers to a compound that is transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Transformation can occur by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative and / or reductive metabolism, etc.) at various locations (e.g., within the intestinal lumen or during transport through the intestine, blood, or liver). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0078] Cyclic urea thiazolyl compounds In one aspect, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] but, [ka] is selected from the group consisting of [ka] but, [ka] is selected from the group consisting of X is CR 2 or N, X 0 is O, S or NR x and X 1 , X 2 , X 3 , X 4 and X 6 is independently selected from the group consisting of O and S; X 5is CH2, CF2, O, S or NR y and L, [ka] and L 1 is a bond, or [ka] but [ka] If L 1 is —CH— or CH(CH)—, L 2 is -CH2-, -CH2CH2- or -CH2CH2CH2-, R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j are independently hydrogen, halo, cyano, OH, NR n R m , -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NR n R m , -SO2NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, and R 13 wherein R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j Only one of the R13 or the two R groups together with the carbon atom to which they are attached can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] Forming a base, R x and R y are independently hydrogen, C 1-4 selected from the group consisting of alkyl, and acetyl; R 1 but, [ka] and R 2 But hydrogen, halo, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy or haloC 1-4 is an alkoxy, R 3 is, for each occurrence, independently selected from the group consisting of halo and cyano; R 3a , R 4a , R 11a , R 12a , and R 14a are independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl and hydroxy C 1-4 is selected from the group consisting of alkyl, R 4 for each occurrence independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 alkenyl, optionally hydroxy C 1-3 Alkyl-substituted C 2-4 alkynyl, cyclopropyl optionally substituted with halo or cyano, and R 4b and wherein one R 4 Only the group R 4bIt can be, R 4b but, [ka] is selected from the group consisting of R 7 and R 8 are independently hydrogen, C 1-4 Alkyl, acetyl, C 3-6 R is selected from the group consisting of monocycloalkyl, phenyl, and pyridyl; 7 and R 8 together with the N atom to which they are attached form an azidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl group; R 7a and R 8a are independently hydrogen, C 1-4 Alkyl and C 3-6 monocycloalkyl, or R 7 and R 8 together with the N atom to which they are attached form an azidinyl, azetidinyl, pyrrolidinyl, or piperidinylmorpholinyl or thiomorpholinyl group, R 9 and R 9a But independently, C 1-4 Alkyl and HaloC 1-4 is selected from the group consisting of alkyl, R 10 and R 10a are independently hydrogen and C 1-4 is selected from the group consisting of alkyl, R 11 , R 12 , and R 14 for each occurrence independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 selected from the group consisting of alkynyl, and cyclopropyl; R 13 but, [ka] is selected from the group consisting of R n and R m for each occurrence independently, hydrogen and C 1-4 is selected from the group consisting of alkyl, j, p, q, r, and x are independently selected from the group consisting of 0 and 1; k, n, s, w, and z are independently selected from the group consisting of 0, 1, and 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein m, t, u, v, and y are independently selected from the group consisting of 0, 1, 2, and 3.

[0079] In another aspect, the present disclosure provides a compound of formula Ia [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] but, [ka] and [ka] but, [ka] and X is CR 2 or N, X 5 is CH2, CF2, O, S or NR y and L, [ka] and R a , Rb , R c , R d , R e , R f , R g and R h are independently hydrogen, halo, cyano, OH, NR n R m , -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NR n R m , -SO2NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, and R 13 wherein R a , R b , R c , R d , R e , R f , R g and R h Only one of the R 13 or the two R groups together with the carbon atom to which they are attached can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] Forming a base, R y But hydrogen, C 1-4 alkyl or acetyl; R 1 but, [ka] and R 2 But hydrogen, halo, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy or haloC 1-4 is an alkoxy, R 3is, for each occurrence, independently selected from the group consisting of halo and cyano; R 4 for each occurrence independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 alkenyl, optionally hydroxy C 1-3 Alkyl-substituted C 2-4 selected from the group consisting of alkynyl, and cyclopropyl optionally substituted with halo or cyano; R 7 and R 8 are independently hydrogen, C 1-4 Alkyl, acetyl, C 3-6 R is selected from the group consisting of monocycloalkyl, phenyl, and pyridyl; 7 and R 8 together with the N atom to which they are attached form an azidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl group; R 7a and R 8a are independently hydrogen, C 1-4 Alkyl and C 3-6 monocycloalkyl, or R 7 and R 8 together with the N atom to which they are attached form an azidinyl, azetidinyl, pyrrolidinyl, or piperidinylmorpholinyl or thiomorpholinyl group, R 9 and R 9a But independently, C 1-4 Alkyl and HaloC 1-4 is selected from the group consisting of alkyl, R 10 and R 10a are independently hydrogen and C 1-4 is selected from the group consisting of alkyl, R 13 but, [ka] is selected from the group consisting of R 14 for each occurrence independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 selected from the group consisting of alkynyl, and cyclopropyl; R 14a But hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl and hydroxy C 1-4 is selected from the group consisting of alkyl, R n and R m for each occurrence independently, hydrogen and C 1-4 is selected from the group consisting of alkyl, j is selected from the group consisting of 0 and 1; k is selected from the group consisting of 0, 1 and 2; wherein m, u, and v are independently selected from the group consisting of 0, 1, 2, and 3, or a pharmaceutically acceptable salt thereof.

[0080] The following embodiments further describe compounds of Formula I, Formula Ia, or pharmaceutically acceptable salts thereof. It will be understood that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the present invention.

[0081] In certain embodiments, [ka] teeth, [ka] is.

[0082] In certain embodiments, [ka] teeth, [ka] is.

[0083] In certain embodiments, [ka] teeth, [ka] is.

[0084] In certain embodiments, [ka] teeth, [ka] is.

[0085] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0086] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0087] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0088] In certain embodiments, [ka] teeth, [ka] is.

[0089] In certain embodiments, [ka] teeth, [ka] is.

[0090] In certain embodiments, [ka] teeth, [ka] is.

[0091] In certain embodiments, [ka] teeth, [ka] is.

[0092] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0093] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0094] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0095] In certain embodiments, L is [ka] is.

[0096] In certain embodiments, L is [ka] is.

[0097] In certain embodiments, L is [ka] is.

[0098] In certain embodiments, L is [ka] is.

[0099] In certain embodiments, L is [ka] is.

[0100] In certain embodiments, L is [ka] is.

[0101] In certain embodiments, L is [ka] is.

[0102] In certain embodiments, L is [ka] is.

[0103] In certain embodiments, X is CR 2 is.

[0104] In certain embodiments, X is CR 2 and R 2 is Cl, F, CH3 or CF3.

[0105] In certain embodiments, X is CR 2 and R 2 is CH3.

[0106] In certain embodiments, R 1 teeth, [ka] is.

[0107] In certain embodiments, R 1 teeth, [ka] is.

[0108] In certain embodiments, R 1 teeth, [ka] is.

[0109] In certain embodiments, R 1 teeth, [ka] is.

[0110] In certain embodiments, R 1 teeth, [ka] is.

[0111] In certain embodiments, R 1 teeth, [ka] is.

[0112] In certain embodiments, R 1 teeth, [ka] is.

[0113] In certain embodiments, R 1 teeth, [ka] is.

[0114] In certain embodiments, R 1 teeth, [ka] is.

[0115] In certain embodiments, R 1 teeth, [ka] is.

[0116] In certain embodiments, R 3 is a halo for each occurrence and u is 1, 2, or 3.

[0117] In certain embodiments, R 3 is F for each occurrence and u is 1, 2, or 3.

[0118] In certain embodiments, R 4 is, for each occurrence, independently selected from the group consisting of halo, CN, methyl, CHF2, CF3, acetylenyl, and cyclopropyl.

[0119] In certain embodiments, R 4 is, for each occurrence independently, halo, CN, OH, NH2, NH(CH3), N(CH3)2, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 alkenyl, optionally hydroxy C 1-3 Alkyl-substituted C 2-4 It is selected from the group consisting of alkynyl, and cyclopropyl optionally substituted with halo or cyano.

[0120] In certain embodiments, R 4b teeth, [ka] is selected from the group consisting of:

[0121] In certain embodiments, R 4b teeth, [ka] is selected from the group consisting of:

[0122] In certain embodiments, R a , R b , R c , R d , R e , R f , R g , R h , R i and R j are independently hydrogen, halo, cyano, OH, NH2, NH(CH3), N(CH3)2, -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -SO2NH2, -SO2NH(CH3), -SO2N(CH3)2, C 1-4 Alkyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl and C 1-4 alkoxy is selected from the group consisting of:

[0123] In certain embodiments, R 13 teeth, [ka] is selected from the group consisting of:

[0124] In certain embodiments, R 13 teeth, [ka] is selected from the group consisting of:

[0125] In another aspect, the present invention provides a compound of formula II [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] but, [ka] and [ka] but, [ka] [ka] is selected from the group consisting of X 2 and X 4 is independently selected from the group consisting of O and S; X 5 is CH2, CF2, O, S or NR y and L, [ka] and L 1 is a bond, or [ka] but [ka] If L 1 is -CH2-, R a , R b , R c , R d , R e , R f , R g , and R h are independently hydrogen, halo, CN, OH, NR n R m , -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NR n R m , -SO2NR n R m , C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, HaloC 1-4 Alkyl, hydroxy C 1-4 Alkyl, and C 1-4 alkoxy, or two R groups together with the carbon atoms to which they are attached are selected from the group consisting of C 3-6 monocycloalkyl, [ka] Forming a base, R n and R m for each occurrence independently, hydrogen and C 1-4 is selected from the group consisting of alkyl, R y But hydrogen, C 1-4 alkyl or acetyl; R 1 but, [ka] and R 2 But hydrogen, halo, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl or haloC 1-4 is an alkoxy, R 4 for each occurrence independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 alkenyl, optionally hydroxy C 1-3 Alkyl-substituted C 2-4 alkynyl, cyclopropyl optionally substituted with halo or cyano, and R 4b and wherein one R 4 Only the group R 4b It can be, R 4aBut hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl and hydroxy C 1-4 is alkyl, R 4b but, [ka] is selected from the group consisting of R 7 and R 8 are independently hydrogen, OH, acetyl, C 1-10 Alkyl, HaloC 1-10 Alkyl, Hydroxy C 1-10 Alkyl, C 1-4 Alkoxy C 1-10 Alkyl, C 3-6 monocycloalkyl, phenyl, pyridyl, or indolyl, or R 7 and R 8 together with the N atom to which they are attached form an arizidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl group, which arizidinyl, azetidinyl, pyrrolinyl, or piperidinyl group is optionally substituted with halo, CN, or OH; R 7a and R 8a are independently hydrogen, C 1-4 Alkyl and C 3-6 monocycloalkyl; or R 7 and R 8 together with the N atom to which they are attached form an azidinyl, azetidinyl, pyrrolidinyl, or piperidinylmorpholinyl or thiomorpholinyl group, R 9 and R 9a But independently, C 1-4 Alkyl and HaloC 1-4 is selected from the group consisting of alkyl, R 10 and R 10a are independently hydrogen and C 1-4 is selected from the group consisting of alkyl, R 11However, independently, halo, CN, OH, NR n R m , C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 selected from the group consisting of alkynyl, and C monocycloalkyl; R 11a But hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl and hydroxy C 1-4 is alkyl, q and x are independently selected from the group consisting of 0 and 1; w and z are independently selected from the group consisting of 0, 1 and 2; wherein v and y are independently selected from the group consisting of 0, 1, 2 and 3, or a pharmaceutically acceptable salt thereof.

[0126] The following embodiments further describe compounds of Formula II, or pharmaceutically acceptable salts thereof. It will be understood that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the present invention.

[0127] In certain embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] is selected from the group consisting of:

[0128] In certain embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] is.

[0129] In certain embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] is selected from the group consisting of:

[0130] In certain embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] is selected from the group consisting of:

[0131] In certain embodiments, [ka] is, s [ka] and [ka] teeth, [ka] is.

[0132] In certain embodiments, L is [ka] is.

[0133] In certain embodiments, L is [ka] is.

[0134] In certain embodiments, L is [ka] is.

[0135] In certain embodiments, L is [ka] is.

[0136] In certain embodiments, L is [ka] is.

[0137] In certain embodiments, R 2 are H, Cl, F, and CH 3、 or CF3.

[0138] In certain embodiments, R 2 is CH3.

[0139] In certain embodiments, R 1 teeth, [ka] is.

[0140] In certain embodiments, R 1 teeth, [ka] is.

[0141] In certain embodiments, R 1 teeth, [ka] is.

[0142] In certain embodiments, R 1 teeth, [ka] is.

[0143] In certain embodiments, R 1 teeth, [ka] is.

[0144] In certain embodiments, R 1 teeth, [ka] is.

[0145] In certain embodiments, R 1 teeth, [ka] is.

[0146] In certain embodiments, R 1 teeth, [ka] is.

[0147] In certain embodiments, R 1 teeth, [ka] is

[0148] In certain embodiments, R 3 is a halo for each occurrence, and u is 0, 1, 2, or 3.

[0149] In certain embodiments, u is 0.

[0150] In certain embodiments, R 4 is, for each occurrence, independently selected from the group consisting of halo, CN, methyl, CHF2, CF3, acetylenyl, and cyclopropyl.

[0151] In certain embodiments, R 4 is, for all occurrences, independently selected from halo.

[0152] How to use The compounds according to the invention are useful in the treatment and prevention of disorders caused by herpes viruses, particularly herpes simplex viruses.

[0153] In one aspect, the invention provides a method of treating or preventing an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the infection is a herpes simplex infection.

[0155] In some embodiments, the infection is an HSV-1 infection.

[0156] In some embodiments, the infection is an HSV-2 infection.

[0157] In some embodiments, the infection is a herpes simplex infection and the subject exhibits symptoms such as cold sores, genital herpes, HSV-associated keratitis, encephalitis, or pneumonia.

[0158] In another embodiment, the infection is a herpes simplex infection and the subject exhibits a condition such as a suppressed immune system (e.g., AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients).

[0159] In another embodiment, the infection is a herpes simplex infection and the subject is a newborn or infant.

[0160] In another aspect, the invention provides a method of suppressing the recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the infection is a herpes simplex infection.

[0162] In some embodiments, the infection is an HSV-1 infection.

[0163] In some embodiments, the infection is an HSV-2 infection.

[0164] In some embodiments, the subject is a herpes positive patient.

[0165] In some embodiments, the subject is a herpes simplex positive patient.

[0166] In another aspect, the invention provides a method of treating or preventing an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the infection is resistant to nucleoside antiviral therapy.

[0167] In one embodiment, the infection is a herpes simplex infection.

[0168] In some embodiments, the infection is a herpes simplex infection.

[0169] In another embodiment, the subject is a herpes positive patient.

[0170] In another embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

[0171] In another aspect, the present invention provides a compound for use as a pharmaceutical.

[0172] Combination therapy The compounds according to the invention, in combination with other active ingredients, are also useful in the treatment and prevention of disorders caused by herpes viruses, particularly herpes simplex viruses.

[0173] In one aspect, the invention provides a method of treating or preventing an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an antiviral agent.

[0174] In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine.

[0175] In some embodiments, the infection is a herpes simplex infection.

[0176] In some embodiments, the infection is an HSV-1 infection.

[0177] In some embodiments, the infection is an HSV-2 infection.

[0178] In some embodiments, the infection is a herpes simplex infection and the subject exhibits symptoms such as cold sores, genital herpes, HSV-associated keratitis, encephalitis, or pneumonia.

[0179] In another embodiment, the infection is a herpes simplex infection and the subject exhibits a condition such as a suppressed immune system (e.g., AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients).

[0180] In another embodiment, the infection is a herpes simplex infection and the subject is a newborn or infant.

[0181] In another aspect, the invention provides a method for suppressing the recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an antiviral agent.

[0182] In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine.

[0183] In some embodiments, the infection is a herpes simplex infection.

[0184] In some embodiments, the infection is an HSV-1 infection.

[0185] In some embodiments, the infection is an HSV-2 infection.

[0186] In some embodiments, the subject is a herpes positive patient.

[0187] In some embodiments, the subject is a herpes simplex positive patient.

[0188] In another aspect, the present invention provides a compound for use as a pharmaceutical.

[0189] In another aspect, the present invention provides a method of treating or preventing an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a corticosteroid.

[0190] In some embodiments, the infection is a herpes simplex infection.

[0191] In some embodiments, the infection is an HSV-1 infection.

[0192] In some embodiments, the infection is an HSV-2 infection.

[0193] In some embodiments, the infection is a herpes simplex infection and the subject exhibits symptoms such as cold sores, genital herpes, HSV-associated keratitis, encephalitis, or pneumonia.

[0194] In another embodiment, the infection is a herpes simplex infection and the subject exhibits a condition such as a suppressed immune system (e.g., AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients).

[0195] In another embodiment, the infection is a herpes simplex infection and the subject is a newborn or infant.

[0196] In another aspect, the invention provides a method for suppressing the recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a corticosteroid.

[0197] In some embodiments, the infection is a herpes simplex infection.

[0198] In some embodiments, the infection is an HSV-1 infection.

[0199] In some embodiments, the infection is an HSV-2 infection.

[0200] In some embodiments, the subject is a herpes positive patient.

[0201] In some embodiments, the subject is a herpes simplex positive patient.

[0202] In another aspect, the present invention provides a compound for use as a pharmaceutical.

[0203] Formulation and Administration The compounds of the present invention can be converted in a known manner using inert, non-toxic, pharmaceutically suitable carriers and solvents into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, where the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e., in an amount sufficient to achieve the indicated dosage range.

[0204] The formulations are prepared, for example, by extending the active compound with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants; for example, if the diluent used is water, organic solvents can be used as co-solvents, if appropriate.

[0205] Administration is by any conventional means, including orally, parenterally, topically, sublingually or intravenously.

[0206] For parenteral administration, solutions or suspensions of the active compounds using suitable liquid carriers and excipients may be employed.

[0207] In general, to achieve effective results, it has proven advantageous to administer an amount of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg body weight in the case of intravenous administration, and for oral administration, the dose is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg body weight.

[0208] In some cases, it may be necessary to deviate from the stated amount, namely depending on body weight or type of administration route, individual response to the drug, its formulation type, and the time or interval of administration.Therefore, it may be appropriate to manage below the above-mentioned minimum amount in some cases, and it may be necessary to exceed the stated upper limit in other cases.When administering a relatively large amount, it may be advisable to divide it into several individual doses throughout the day.

[0209] If desired, it may be useful to combine the compounds according to the invention with other active substances, in particular antiviral active substances.

[0210] The compounds used in the present invention may be in the form of pharmaceutically acceptable salts, cocrystals, or solvates. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic and organic bases or acids. When a compound of the present invention contains one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compound, particularly pharmaceutically acceptable salts of the compound. Thus, compounds of the present invention containing acidic groups can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts of ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of the present invention containing one or more basic groups, i.e., protonatable groups, can be used in accordance with the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms mentioned above, inner salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which are not directly suitable for use in medicines because of their poor physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0211] Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms that act as image and mirror image (enantiomers) or that do not act as image and mirror image (diastereomers). The present invention relates to both the enantiomers or diastereomers and their respective mixtures. As with diastereomers, racemic forms can be separated into stereoisomerically uniform components by known methods.

[0212] The scope of the present invention includes compounds which, once inside the body, are simply converted to the actual active compound of formula I (so-called prodrugs).

[0213] In practice, the compounds used in the present invention can be combined as active ingredients in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired, for example, for oral or parenteral (including intravenous) administration. When preparing compositions for oral dosage forms, for example, for oral liquid preparations such as suspensions, elixirs and solutions, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used; for example, for oral solid preparations such as powders, hard and soft capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., can be used; solid oral preparations are preferred over liquid preparations.

[0214] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compound can also be administered intranasally, for example, as liquid drops or spray, or as eye drops.

[0215] Tablets, pills, capsules, etc. may also contain binders such as hydroxypropylmethylcellulose or polyvinylpyrrolidone, diluents or fillers such as microcrystalline cellulose, dicalcium phosphate, lactose, or mannitol, disintegrants such as croscarmellose sodium, polyvinylpyrrolidone, or sodium starch glycolate, lubricants such as magnesium stearate or sodium stearyl fumarate, glidants such as silicon dioxide, and sweeteners such as sucrose or saccharin. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0216] Various other materials may be present as coatings or may modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0217] The compounds used in the present invention can be administered parenterally.These active compounds can be prepared in water, suitably mixed with surfactants such as hydroxypropyl cellulose, sodium lauryl sulfate, or polysorbate, in solution or suspension.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0218] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0219] Any suitable route of administration can be used to provide a mammal, particularly a human, with an effective dose of the compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, and the like may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The compound of the present invention may be administered orally or as eye drops. The compound of the present invention may also be administered orally. The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one skilled in the art.

[0220] The compounds of the present invention may be present in combination with additional active ingredients, particularly one or more active ingredients that exhibit beneficial effects in the treatment of any of the disorders or diseases described herein. The compounds of the present invention may be present in a composition (i.e., combination therapy) in combination with at least one additional active substance (antiviral active compound) that is effective in treating a disease or disorder associated with a viral infection, preferably a disease or disorder associated with a viral infection caused by a herpes virus, particularly a herpes simplex virus. The at least one additional active substance (antiviral active compound) that is effective in treating a disease or disorder associated with a viral infection is preferably selected from the group consisting of nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir, and trifluridine, and compounds such as foscarnet and cidofovir.

[0221] Thus, the present invention relates to pharmaceutical compositions comprising one or more of the compounds described herein and at least one pharmaceutically acceptable carrier and / or excipient, and / or at least one further active substance (antivirally active compound) that is effective in the treatment of a disease or disorder associated with a viral infection.

[0222] The novel active compounds can be converted in known manner into customary preparations such as tablets, caplets, dragees, pills, granules, aerosols, syrups, pharmaceutically suitable carriers, and solvents, where the therapeutically active compound should in each case be present in a concentration of about 0.1 to 90% by weight of the total mixture, i.e., in an amount sufficient to achieve the indicated dosage range.

[0223] The formulations are prepared, for example, by extending the active compound with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants; for example, if the diluent used is water, organic solvents can be used as co-solvents, if appropriate.

[0224] Administration is effected in the customary manner, preferably orally, parenterally or topically, in particular sublingually or intravenously.

[0225] For parenteral administration, solutions or suspensions of the active compounds using suitable liquid carrier materials may be employed.

[0226] In general, to achieve effective results, it has proven advantageous to administer an amount of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg body weight in the case of intravenous administration, and for oral administration, the dose is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg body weight.

[0227] Nevertheless, it may be necessary to deviate from the stated amount in appropriate cases, i.e., depending on body weight or type of administration route, individual response to the drug, its formulation, and the time or interval of administration.Therefore, it may be appropriate to manage below the above-mentioned minimum amount in some cases, or it may be necessary to exceed the stated upper limit.When administering a relatively large amount, it may be advisable to divide it into several individual doses throughout the day. [Example]

[0228] The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, unless otherwise indicated, it should be understood that all proposed reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and workup procedures, can be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods will be shown accordingly. The starting materials of the examples are commercially available or can be easily prepared from known materials by standard methods.

[0229] At least some of the compounds identified herein as "intermediates" are contemplated as compounds of the present disclosure. [Table 5]

[0230] The following LCMS method was used for the analysis of the final compounds. Method A: X-Bridge BEH C-18 (3 × 50 mm × 2.5 mm); Mobile phase: A: 0.025% formic acid in H2O; B: CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 2% B to 98% B in 2.2 min, hold for 3 min, B concentration at 2% in 3.2 min, hold for 4 min.

[0231] Method B: X-select CSH 18 (3 × 50 mm × 2.5 mm); Mobile phase: A: 0.025% formic acid in H2O; B: CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, 0% B in 3.2 min, hold for 4 min.

[0232] Method C: X-select CSH 18 (3 × 50 mm × 2.5 mm); Mobile phase: A: 0.05% formic acid in H2O:CH3CN (95:5); B: 0.05% formic acid in CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, 0% B in 3.2 min, hold for 4 min.

[0233] Method D: X-select CSH C18 (3 × 50 mm × 2.5 μm); Mobile phase: A; 2 mM in ammonium bicarbonate; B; CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, 0% B in 3.2 min, hold for 4 min.

[0234] Method E: X-select CSH 18 (3 × 50 mm × 2.5 mm); Mobile phase: A: 0.05% formic acid in H2O; B: CH3CN; Injection volume: 2 μL; Flow rate: 1.5 mL / min; Column temperature: 50 °C; Gradient program: 0% B to 100% B in 1.5 min, hold for 2.2 min, 0% B in 2.6 min, hold for 3 min.

[0235] Example 1. 4-Methyl-2-(2-oxo-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (1) [ka] Step 1. Synthesis of 5-(benzylthio)-4-methylthiazol-2-amine (1-2) Benzyl mercaptan (15.8 mL, 134.70 mmol) was added dropwise to a stirred solution of 1-1 (20 g, 103.62 mmol) in ethanol (200 mL) at 0 °C. The resulting reaction mixture was slowly warmed to room temperature and stirred at 80 °C for 3 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in EtOAc, and the organic layer was washed with water. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluting with 10-20% EtOAc in heptane) to give 1-2 (25 g, 93.9%) as a dark brown sticky solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 11 H 12 Calculated for N2S2: 236.04; Found: 236.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ 7.35-7.17(m,3H),7.12(dd,J=1.6,7.8Hz,2H),7.06(s,2H),3.77(s,2H),1.73(s,3H)ppm.

[0236] Step 2. Synthesis of 1-(5-(benzylthio)-4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (1-3) A mixture of 1-chloro-3-isocyanatopropane (1.29 g, 10.847 mmol) and compound 1-2 (2 g, 8.474 mmol) in THF (100 mL) was heated at 65 °C for 7 h. While maintaining the same temperature, TBAI (0.15 g, 0.423 mmol) and K2CO3 (1.43 g, 11.016 mmol) were added portionwise to the resulting solution, and stirring was continued at 65 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 60-70% EtOAc in heptane) to give 1-3 (1.3 g, 48.1%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS(ESI):C 15 H 17 Calculated for N3OS2: 319.08; Measured: 320.10 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.45(br s,1H),7.30-7.20(m,3H),7.19-7.03(m,2H),3.93(t,J=5.6Hz,2H),3.84(s,2H),3.23-3.17(m,2H),1.89(s,3H)ppm.

[0237] Step 3. Synthesis of 1-(5-(benzylthio)-4-methylthiazol-2-yl)-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-2(1H)-one (1-4) To a stirred solution of 1-3 (0.8 g, 2.50 mmol) in 1,4-dioxane (12 mL) was added compound 1-7 (0.6 g, 2.75 mmol), K2CO3 (0.7 g, 5.00 mmol), and 1,2-dimethylethylenediamine (0.11 g, 1.25 mmol). The reaction mixture was purged under nitrogen for 10 minutes. CuI (0.095 g, 0.50 mmol) was then added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by reverse-phase CombiFlash® chromatography (eluting with 25% ACN in 0.01 M HCOOH in water) to give 1-4 (0.5 g, 42.3%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.5). MS(ESI):C 26 H 24 Calculated for N4OS2: 472.14; Found: 473.2 [M+1] + .

[0238] Step 4. Synthesis of 2-(4-bromophenyl)pyridine (1-7) To a stirred solution of 2-bromopyridine 1-6 (3 g, 18.987 mmol) in toluene:HO:EtOH (1:1:0.2, 150 mL) was added (4-bromophenyl)boronic acid 1-5 (4.9 g, 24.683 mmol) and NaCO (14.90 g, 140.50 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(PPh) (0.66 g, 0.576 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 20-30% EtOAc in heptane) to give 1-7 (2 g, 45%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS(ESI):C 11 Calculated for HBrN: 232.98; Found: 235.98 [M+2] + . 1 H NMR (400MHz, CDCl3): δ 8.69(d,J=4.8Hz,1H),7.92-7.84(m,2H),7.80-7.73(m,1H),7.73-7.69(m,1H),7.63-7.57(m,2H),7.30-7.23(m,1H)ppm.

[0239] Step 5. Synthesis of 4-methyl-2-(2-oxo-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (1) To a stirred solution of 1-4 (0.3 g, 0.635 mmol) in AcOH / HO (2.8 / 0.15 mL) was added NCS (0.31 g, 2.38 mmol), and the reaction mixture was stirred at room temperature for 15 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in THF (5 mL), and aqueous ammonia (3 mL) was added, while stirring was continued at room temperature for another 4 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM, and the organic layer was washed with water. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by reverse-phase CombiFlash® chromatography (eluted with 10% ACN in 0.01 M HCOOH in water) to give 1 (26 mg, 9.5%) as an off-white solid. TLC: 100% EtOAc (R f :0.5).

[0240] Example 2. 2-(3-(5'-ethynyl-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (17) [ka] Step 1. Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (2-2) A mixture of 2-1 (10 g, 87.71 mmol) and 1-chloro-3-isocyanatopropane (15.5 g, 131.57 mmol) in THF (150 mL) was heated at 70 °C for 6 h. While maintaining the same temperature, TBAB (1.4 g, 4.38 mmol) and K2CO3 (15.73 g, 114.02 mmol) were added portionwise to the resulting solution, and stirring was 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 (eluted with 60-70% EtOAc in heptane) to give 2-2 (10 g, 57.6%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS(ESI):C8H 11 Calculated value for N3OS: 197.06; Measured value: 198.17 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ 7.30(s,1H),6.60(s,1H),3.99(t,J=5.4Hz,2H),3.20-3.19(m,2H),2.28(s,3H),1.99-1.89(m,2H)ppm.

[0241] Step 2. Synthesis of 1-(4-bromophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (2-3) To a stirred solution of 2-2 (5 g, 25.25 mmol) in 1,4-dioxane (200 mL) was added 1-bromo-4-iodobenzene (14 g, 50.5 mmol), K2CO3 (6.9 g, 50.5 mmol), and 1,2-dimethylethylenediamine (1 g, 12.62 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. CuI (0.95 g, 5.05 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with 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 50-70% EtOAc in heptane) to give 2-3 (2.5 g, 28.4%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5). MS(ESI):C 14 H 14 Calculated for BrN3OS: 351.00; Found: 354.09 [M+2] + .

[0242] Step 3. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (2-4) To a stirred solution of 2-3 (2 g, 5.68 mmol) in dry DCM (20 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (1.3 g, 11.363 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The precipitated solid was collected by filtration and dried under vacuum to give 2-4 (2 g, 81.9%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5) was used in the next step without further purification. MS (ESI): C 14 H 14Calculated for BrN3O4S2: 430.96; Found: 434.00 [M+2] +

[0243] Step 4. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (2-5) A mixture of 2-4 (1 g, 2.315 mmol) and POCl (10 mL) was stirred at 100 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in THF (10 mL) and aqueous ammonia (20 mL) was added at 0 °C, while stirring was continued at room temperature for another 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 2-5 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 14 H 15 Calculated for BrN4O3S2: 429.98; Found: 431.1 [M+1] + .

[0244] Step 5. Synthesis of 4-methyl-2-(2-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (2-6) To a stirred solution of 2-5 (0.6 g, 1.392 mmol) in 1,4-dioxane (20 mL), bis(pinacolato)diborane (0.53 g, 2.088 mmol) and KOAc (0.27 g, 2.784 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. PdCl(dppf) (0.1 g, 0.14 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 120 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30–40% EtOAc in heptane) to give 2-6 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 20 H 27 Calculated for BN4O5S2: 478.15; Found: 479.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.70(d,J=7.8Hz,2H),7.55(s,2H),7.42-7.38(m,2H),4.17-4.09(m,2H),3.82-3.74(m,2H),2.44(s,3H),2.26-2.15(m,2H),1.30(s,9H)ppm.

[0245] Step 6. Synthesis of 2-(3-(5'-bromo-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (2-7) To a stirred solution of 2-6 (0.4 g, 0.836 mmol) in 1,4-dioxane and water (16:4 mL), 4-bromo-1-fluoro-2-iodobenzene (0.25 g, 0.836 mmol) and Na2CO3 (0.17 g, 1.673 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl2 (61 mg, 0.083 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 2-7 (0.2 g, 45.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 20 H 18 Calculated for BrFN4O3S2: 524.00; Found: 525.00 [M+1] + .

[0246] Step 7. Synthesis of 2-(3-(5'-ethynyl-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (17) To a stirred solution of 2-7 (0.1 g, 0.190 mmol) in DMF (5 mL) was added triethylamine (0.1 mL, 0.571 mmol) and CuI (4 mg, 0.019 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(PPh3)2Cl2 (27 mg, 0.038 mmol) and ethynyltrimethylsilane (56 mg, 0.571 mmol) were added under a nitrogen atmosphere, and the reaction mixture was then heated at 120 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give 17 (5 mg, 5.61%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0247] Example 3. 2-(3-(5'-Fluoro-2'-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (19) [ka] Step 1. Synthesis of 4-(2-bromo-4-fluorophenyl)-2-methylbut-3-yn-2-ol (3-2) To a stirred solution of compound 3-1 (1 g, 3.323 mmol) in DIPEA (10 mL) was added 2-methylbut-3-yn-2-ol (0.49 g, 4.984 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (63 mg, 0.332 mmol) and Pd(dppf)Cl (0.11 g, 0.166 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 5–10% EtOAc in heptane) to give 3-2 (0.8 g, 94.1%) as a brown oil. TLC: 10% EtOAc / heptane (R f :0.5).

[0248] Step 2. Synthesis of 2-(3-(5'-fluoro-2'-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (19) To a stirred solution of 2-6 (0.2 g, 0.418 mmol) in 1,4-dioxane:water (4:1, 10 mL) was added 4-(2-bromo-4-fluorophenyl)-2-methylbut-3-yn-2-ol (0.1 g, 0.418 mmol), followed by Na2CO3 (88 mg, 0.836 mmol), and the resulting reaction mixture was purged under nitrogen for 20 minutes. To this resulting reaction mixture, Pd(dppf)Cl2 (30 mg, 0.0418 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give 19 (10 mg, 4.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0249] Example 4. 4-Methyl-2-(2-oxo-3-(3'-(thiazol-5-yl)-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (30) [ka] Step 1. Synthesis of 2-(3-bromophenyl)thiazole (4-2) To a stirred solution of 4-1 (1 g, 6.097 mmol) in 1,4-dioxane:water (4:1, 15 mL) was added (3-bromophenyl)boronic acid (1.34 g, 6.707 mmol), followed by KPO (3.18 g, 15.242 mmol), and the resulting reaction mixture was purged under nitrogen for 20 minutes. To this resulting reaction mixture, Pd(dppf)Cl (0.445 g, 0.6097 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluting with 2-3% EtOAc in heptane) to give 4-2 (0.2 g, 13.7%) as an off-white solid. TLC: 10% EtOAc / heptane (R f :0.5).

[0250] Step 2. Synthesis of 4-methyl-2-(2-oxo-3-(3'-(thiazol-2-yl)-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (30) To a stirred solution of 8 (0.2 g, 0.418 mmol) in 1,4-dioxane:water (4:1, 10 mL) was added 2-(3-bromophenyl)thiazole (0.1 g, 0.418 mmol), followed by KPO (0.221 g, 1.04 mmol), and the resulting reaction mixture was purged under nitrogen for 20 minutes. Pd(dppf)Cl (30.6 mg, 0.041 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give 30 (14 mg, 6.5%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.5).

[0251] Example 5. 4-Methyl-2-(2-oxo-3-(4-(thiazol-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (42) [ka] Step 1. Synthesis of 4-methyl-2-(2-oxo-3-(4-(thiazol-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (42) To a stirred solution of 2-6 (0.15 g, 0.313 mmol) in 1,4-dioxane and water (8:2 mL), 2-bromothiazole (0.1 g, 0.626 mmol) and KPO (0.13 g, 0.626 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (23 mg, 0.0313 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 42 (20 mg, 15.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0252] Example 6. 2-(3-(4-(benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (51) [ka] Step 1. Synthesis of ethyl 4-(3-(4-methylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoate (6-1) To a stirred solution of 2-2 (3.1 g, 15.656 mmol) in 1,4-dioxane (100 mL), ethyl 4-iodobenzoate (4.3 g, 15.656 mmol), K2CO3 (4.3 g, 3.131 mmol), and 1,2-dimethylethylenediamine (0.7 g, 1.269 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Then, CuI (0.6 g, 3.131 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere, and the resulting reaction mixture was heated at 100 °C for 24 hours. After completion of the reaction, the reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50-70% EtOAc in heptane) to give 6-1 (3 g, 57.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 17 H 19 Calculated for N3O3S: 345.1; Found: 346.1 [M+1] + .

[0253] Step 2. Synthesis of 2-(3-(4-(ethoxycarbonyl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (6-2) To a stirred solution of 6-1 (3 g, 8.695 mmol) in dry DCM (50 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (2 g, 17.39 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 6-2 (3 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5) was used in the next step without further purification. MS (ESI): C 17 H19 Calculated for N3O6S2: 425.1; Found: 426.1 [M+1] + .

[0254] Step 3. Synthesis of ethyl 4-(3-(4-methyl-5-sulfamoylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoate (6-3) A mixture of 6-2 (0.5 g, 1.176 mmol) and POCl3 (5 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in THF (5 mL), and aqueous ammonia (8 mL) was added at 0 °C, while stirring was continued at room temperature for another 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5-10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 6-3 (0.3 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5) was used in the next step without further purification. MS (ESI): C 17 H 20 Calculated for N4O5S2: 424.09; Found: 424.92 [M+1] + .

[0255] Step 4. Synthesis of 4-(3-(4-methyl-5-sulfamoylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoic acid (6-4) To a stirred solution of 6-3 (0.2 g, 0.471 mmol) in THF:MeOH:HO (8:1:1 mL) at 0 °C, lithium hydroxide monohydrate (39 mg, 0.943 mmol) was added portionwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was treated with saturated KHSO solution, and the resulting precipitated solid was collected by filtration and dried in vacuo to give 6-4 (0.2 g, crude) as an off-white solid, which was used in the next step without further purification. TLC: 50% EtOAc / heptane (R f :0.5);MS(ESI):C15 H 16 Calculated for N4O5S2: 396.06; Found: 397.2 [M+1] + .

[0256] Step 5. Synthesis of 2-(3-(4-(1,3,4-oxadiazol-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (51) To a stirred solution of 6-4 (0.2 g, 0.505 mmol) in DCM / EtOH (10 / 10 mL) was added (N-isocyanoimino)triphenylphosphorane (0.30 g, 1.010 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the resulting reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 51 (36 mg, 16.9%) as an off-white solid.

[0257] Example 7. 2-(3-(4-(benzo[d]thiazol-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (67) [ka] Step 1. Synthesis of 2-(3-(4-(benzo[d]thiazol-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (67) To a stirred solution of 2-6 (0.2 g, 0.418 mmol) in 1,4-dioxane and water (5 / 0.5 mL) was added 7-bromobenzo[d]thiazole (0.18 g, 0.836 mmol), followed by K2CO3 (0.17 g, 0.836 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting solution, Pd(dppf)Cl2 (30 mg, 0.041 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 120 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 67 (10 mg, 5%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5).

[0258] Example 8. 2-(3-(4-(benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (71) [ka] Step 1. Synthesis of 2-(3-(4-(benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (71) To a stirred solution of 2-6 (0.2 g, 0.418 mmol) in 1,4-dioxane and water (4:1, 10 mL), 4-bromobenzo[d]thiazole (0.13 g, 0.627 mmol) and Na2CO3 (88 mg, 0.836 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting solution, Pd(dppf)Cl2 (30 mg, 0.0406 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 71 (30 mg, 15%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0259] Example 9. 2-(3-(2,5-difluoro-[1,1′-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (99) [ka] Step 1. Synthesis of 1-(4-bromo-2,5-difluorophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (9-1) To a stirred solution of 2-2 (1.5 g, 7.614 mmol) in 1,4-dioxane (30 mL), 1,4-dibromo-2,5-difluorobenzene (3.10 g, 11.42 mmol), K2CO3 (2.1 g, 15.228 mmol), and 1,2-dimethylethylenediamine (0.27 g, 3.045 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (0.3 g, 1.522 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 120 °C for 24 hours. The reaction mixture was filtered through a Celite® 545 bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50-70% EtOAc in heptane) to give 9-1 (0.8 g, 27.1%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 14 H 12 Calculated for BrF2N3OS: 386.99; Found: 390.0 [M+2] + . 1 H NMR(400MHz,DMSO-d6):δ 7.86(dd,J=6.4,9.3Hz,1H),7.67(d,J=2.4Hz,1H),6.72(s,1H),4.16(t,J=5.9Hz,2H),3.69(t,J=5.4Hz,2H),2.25(s,3H),2.23-2.17(m,2H)ppm.

[0260] Step 2. Synthesis of 2-(3-(4-bromo-2,5-difluorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (9-2) To a stirred solution of 9-1 (0.89 g, 2.294 mmol) in dry DCM (20 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.38 g, 5.734 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 9-2 (0.75 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5) was used in the next step without further purification. MS (ESI): C 14 H 12 Calculated for BrF2N3O4S2: 466.94; Found: 469.85 [M+2] + . 1 H NMR (400MHz, DMSO-d6): δ 7.87(t,J=7.1Hz,1H),7.69(t,J=7.1Hz,1H),5.79(br.s,1H),4.22-3.98(m,2H),3.73-3.59(m.2H). 2.32(s,3H),2.27-2.09(m,2H)ppm.

[0261] Step 3. Synthesis of 2-(3-(4-bromo-2,5-difluorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (9-3) A mixture of 9-2 (1 g, 2.136 mmol) and POCl (10 mL) was stirred at 100 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in THF (5 mL) and aqueous ammonia (5 mL) was added at 0 °C, while stirring was continued at room temperature for another 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 9-3 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C14 H 13 Calculated for BrF2N4O3S2: 465.96; Found: 467.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.93-7.85(m,1H),7.70(t,J=7.8Hz,1H),7.57(br.s,2H),4.21-4.12(m,2H),3.77-3.67(m,2H),2.44(s,3H),2.27-2.17(m,2H)ppm.

[0262] Step 4. Synthesis of 2-(3-(2,5-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (99) To a stirred solution of 9-3 (0.2 g, 0.428 mmol) in 1,4-dioxane and water (4:1 mL) was added phenylboronic acid (78 mg, 0.642 mmol) and Na2CO3 (90 mg, 0.856 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl2 (31 mg, 0.043 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 12 hours. The reaction mixture was filtered through a Celite bed, washed with ethyl acetate, and the resulting filtrate was concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash® chromatography (eluting with 80-90% EtOAc in heptane) to give 99 (0.12 g, 60.6%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0263] Example 10. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,3-diazepan-1-yl)-4-methylthiazole-5-sulfonamide (101) [ka] Step 1. Synthesis of 4-((4-methylthiazol-2-yl)amino)butan-1-ol (10-2) To a stirred solution of 10-1 (5 g, 37.593 mmol) in DMSO (50 mL) was added K2CO3 (7.78 g, 56.390 mmol), 4-aminobutan-1-ol (6.66 g, 75.186 mmol), followed by CuI (0.71 g, 3.759 mmol). The resulting reaction mixture was heated at 100 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite® 545, and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 20-30% EtOAc in heptane] to give 10-2 (4 g, 28.7%) as a light brown oil. TLC: 20% EtOAc / heptane (R f : 0.2). MS(ESI): C8H 14 Calculated value for N2OS: 186.27; Measured value: 187.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.37(br s,1H),6.10(s,1H),4.40(t,J=4.6Hz,1H),3.45-3.35(m,2H),3.21-3.09(m,2H),2.07(s,3H),1.60-1.41(m,4H)ppm.

[0264] Step 2. Synthesis of 3-(4-bromophenyl)-1-(4-hydroxybutyl)-1-(4-methylthiazol-2-yl)urea (10-3) To a stirred solution of 10-2 (1.5 g, 8.064 mmol) in 1,4-dioxane (30 mL), compound 1-bromo-4-isocyanatobenzene (1.6 g, 8.064 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® column chromatography [eluted with 30-40% EtOAc in heptane] to give 10-3 (1.1 g, 38.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.2). MS(ESI):C 15 H 18 Calculated for BrN3O2S: 383.03; Found: 386 [M+2] + .

[0265] Step 3. Synthesis of 4-(3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)ureido)butyl 4-methylbenzenesulfonate (10-4) To a stirred solution of 10-3 (1.0 g, 2.604 mmol) in DCM (20 mL) was added triethylamine (0.55 mL, 3.906 mmol), followed by tosyl chloride (0.6 g, 3.125 mmol) at 0 °C. The resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 30-40% EtOAc in heptane] to give 10-4 (1 g, 71.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 22 H 24 Calculated for BrN3O4S2: 537.04; Found: 538.14 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 10.05(s,1H),7.75(d,J=8.3Hz,2H),7.55-7.46(m,4H),7.46-7.41(m,2H),6. 78(s,1H),4.15-4.03(m,4H),2.39(s,3H),2.27(s,3H),1.66-1.58(m,4H)ppm.

[0266] Step 4. Synthesis of 1-(4-bromophenyl)-3-(4-methylthiazol-2-yl)-1,3-diazepan-2-one (10-5) To a stirred solution of 10-4 (1 g, 1.858 mmol) in dry DMF (10 mL) at 0 °C under a nitrogen atmosphere, NaH (60% w / w in mineral oil, 0.134 g, 2.788 mmol) was added in small portions, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 15 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 10-5 (0.6 g, 88.2%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5) was used in the next step without further purification. MS (ESI): C 15 H 16 Calculated for BrN3OS: 365.02; Found: 368 [M+2] + . 1 H NMR(400MHz,DMSO-d6):δ 7.55(d,J=8.8Hz,2H),7.31(d,J=8.8Hz,2H),6.66(s,1H),4.24-4.16(m,2H) ),3.73-3.64(m,2H),2.24(s,3H),1.96-1.86(m,2H),1.84-1.74(m,2H)ppm.

[0267] Step 5. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)-1,3-diazepan-2-one (10-6) To a stirred solution of 10-5 (0.6 g, 1.639 mmol) in 1,4-dioxane was added HO (4:1, 20 mL), (2,5-difluorophenyl)boronic acid (0.38 g, 2.46 mmol), and CsCO (1 g, 3.278 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(PPh)Cl (0.12 g, 3.278 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 0 to 30% EtOAc in heptane) to give 10-6 (0.6 g, 92.3%) as a yellow solid. TLC: 30% EtOAc / heptane (R f :0.5). MS(ESI):C 21 H 19 Calculated for F2N3OS: 399.12; Measured: 400.05 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.60(d,J=7.8Hz,2H),7.47(d,J=7.8Hz,3H),7.44-7.34(m,1H),7.34-7.19(m,1H),6.69(s,1H) ),4.28-4.20(m,2H),3.82-3.75(m,2H),2.26(s,3H),2.00-1.90(m,2H),1.87-1.77(m,2H)ppm.

[0268] Step 6. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,3-diazepan-1-yl)-4-methylthiazole-5-sulfonic acid (10-7) To a stirred solution of 10-6 (0.3 g, 0.751 mmol) in dry DCM (10 mL) at -5 °C under an inert atmosphere, chlorosulfuric acid (0.15 mL, 2.255 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried in vacuo to give 10-7 (0.6 g, 88.2%) as an off-white solid, which was used in the next step without further purification. TLC: 30% EtOAc / heptane (R f :0.5). MS(ESI):C 21 H 19 Calculated for F2N3O4S2: 479.08; Found: 480.21 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.60(d,J=7.8Hz,2H),7.48(d,J=8.3Hz,3H),7.44-7.33(m,1H),7.33-7.19(m,1H),6.10(br s,1H),4.23-4.13(m,2H),3.82-3.73(m,2H),2.34(s,3H),2.00-1.89(m,2H),1.88-1.75(m,2H)ppm.

[0269] Step 7. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,3-diazepan-1-yl)-4-methylthiazole-5-sulfonamide (101) To a stirred solution of 2-7 (0.2 g, 0.417 mmol) in DCM (10 mL) at -10 °C under an inert atmosphere, oxalyl chloride (0.1 mL, 1.252 mmol) was added, followed by DMF (catalytic). The resulting reaction mixture was slowly warmed to room temperature and stirred at 60 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (5 mL), and aqueous ammonia (5 mL) was added at 0 °C, while stirring was continued at room temperature for another 1 h. 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 30-40% EtOAc in heptane), followed by preparative HPLC to give 101 (40 mg, 20%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0270] Example 11. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-sulfonamide (104) [ka] Step 1. Synthesis of 4'-bromo-2,5-difluoro-1,1'-biphenyl (11-7) To a stirred solution of 11-6 (5 g, 17.674 mmol) in 1,4 dioxane / HO (50 mL / 5 mL), (2,5-difluorophenyl)boronic acid (11-5) (3.07 g, 19.441 mmol) and KPO (7.5 g, 35.348 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. PdCl(dppf) (1.29 g, 1.767 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite® 545, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 100% heptane) to give 11-7 (2.3 g, 48.6%) as an off-white solid. TLC: 100% heptane (R f :0.5). 1 H NMR(400MHz,CDCl3)δ 7.58(d,J=8.3Hz,2H),7.40(d,J=7.3Hz,2H),7.15-7.06(m,2H),7.05-6.97(m,1H)ppm.

[0271] Step 2. Synthesis of 1-(4-methylthiazol-2-yl)imidazolidin-2-one (11-2) A mixture of 2-1 (5 g, 43.859 mmol) and 1-chloro-2-isocyanatoethane (6.9 g, 65.79 mmol) in THF (100 mL) was heated at 65 °C for 5 h. While maintaining the same temperature, TBAB (0.7 g, 2.192 mmol) and K2CO3 (12.10 g, 87.718 mmol) were added portionwise to the resulting solution, and stirring was continued at 65 °C for 16 h. 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 (eluted with 60-70% EtOAc in heptane) to give 11-2 (6 g, 75%) as an off-white solid. TLC: 70% EtOAc / heptane (R f : 0.5). MS (ESI): Calculated for C7H9N3OS: 183.05; Found: 184.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ 7.52(br s,1H),6.65(s,1H),4.00(t,J=7.8Hz,2H),3.48(t,J=8.1Hz,2H),2.21(s,3H)ppm.

[0272] Step 3. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)imidazolidin-2-one (11-3) To a stirred solution of 11-2 (2 g, 10.752 mmol) in 1,4-dioxane (50 mL), 11-7 (5.7 g, 21.505 mmol), K2CO3 (2.96 g, 21.505 mmol), and 1,2-dimethylethylenediamine (0.47 g, 5.376 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (0.4 g, 2.150 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50-70% EtOAc in heptane) to give 11-3 (0.35 g, 17.5%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5). MS(ESI):C 19 H 15 Calculated for F2N3OS: 371.09; Measured: 372.35 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.77(d,J=8.3Hz,2H),7.69-7.57(m,2H),7.49-7.30(m,2H),7.30-7.19(m,1H),6.79(s,1H),4.21-4.05(m,4H),2.28(s,3H)ppm.

[0273] Step 4. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-sulfonic acid (11-4) To a stirred solution of 11-3 (0.3 g, 0.808 mmol) in dry DCM (5 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.16 mL, 2.425 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 11-4 (0.2 g, 66.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5) was used in the next step without further purification.

[0274] Step 5. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-sulfonamide (104) To a stirred solution of 11-4 (0.2 g, 0.442 mmol) in DCM (5 mL) at 0 °C under an inert atmosphere, oxalyl chloride (0.1 mL, 1.327 mmol) was added, followed by DMF (catalytic). The resulting reaction mixture was slowly warmed to room temperature and stirred at 50 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (2 mL), and aqueous ammonia (5 mL) was added at 0 °C, while stirring was continued at room temperature for another 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 0–1% MeOH in DCM) followed by preparative HPLC to give 104 (8 mg, 4.2%) as an off-white solid.

[0275] Example 12. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (107) [ka] Step 1. Synthesis of 3-((4-methylthiazol-2-yl)amino)butan-1-ol (12-1) To a stirred solution of 10-1 (1 g, 7.518 mmol) in DMSO (10 mL) was added 3-aminobutan-1-ol (1.0 g, 11.278 mmol), followed by KCO (2.5 g, 18.795 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (0.142 g, 0.751 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 120 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 30-70% EtOAc in heptane) to give 12-1 (0.35 g, 25%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0276] Step 2. Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-4-methylthiazol-2-amine (12-2) To a stirred solution of 12-1 (1.5 g, 8.064 mmol) in dry DCM (20 mL) at 0 °C under a nitrogen atmosphere, imidazole (1.09 g, 16.128 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 10-15 min. To this reaction mixture, tert-butyldimethylsilyl chloride (1.38 g, 8.870 mmol) was added at 0 °C, and the reaction mixture was then slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 30-40% EtOAc in heptane) to give 12-2 (1 g, 41.6%) as a yellow oil. TLC: 30% EtOAc / heptane (R f :0.5).

[0277] Step 3. Synthesis of 3-(4-bromophenyl)-1-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-1-(4-methylthiazol-2-yl)urea (12-3) To a stirred solution of 12-2 (1 g, 3.333 mmol) in 1,4-dioxane (10 mL) at 0 °C under an inert atmosphere, 1-bromo-4-isocyanatobenzene (0.78 g, 4.00 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 30-40% EtOAc in heptane] to give 12-3 (1 g, 62.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0278] Step 4. Synthesis of 3-(4-bromophenyl)-1-(4-hydroxybutan-2-yl)-1-(4-methylthiazol-2-yl)urea (12-4) To a stirred solution of 12-3 (1 g, 2.012 mmol) in dry THF (5 mL) at 0 °C under a nitrogen atmosphere, tetrabutylammonium fluoride (1 M solution in THF, 4.02 mL, 4.024 mmol) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold 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 20-30% EtOAc in heptane) to give 12-4 (0.5 g, crude) as a pale yellow oil. TLC: 50% EtOAc / heptane (R f :0.5).

[0279] Step 5. Synthesis of 1-(4-bromophenyl)-4-methyl-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (12-5) To a stirred solution of 12-4 (0.5 g, 1.305 mmol) in toluene (5 mL) at 0 °C, triphenylphosphine (0.68 g, 2.610 mmol) was added, followed by DEAD (0.52 g, 2.61 mmol). The resulting reaction mixture was slowly warmed to room temperature and stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 20-30% EtOAc in heptane) to give 12-5 (0.3 g, 62.8) as a pale yellow oil. TLC: 50% EtOAc / heptane (R f :0.5).

[0280] Step 6. Synthesis of 2-(3-(4-bromophenyl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (12-6) To a stirred solution of 12-5 (0.3 g, 0.821 mmol) in dry DCM (5 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.19 mL, 1.643 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give 12-6 (0.25 g, crude) as an off-white solid. TLC: 40% EtOAc / heptane (R f :0.3) was used in the next step without further purification.

[0281] Step 7. Synthesis of 2-(3-(4-bromophenyl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (12-7) A mixture of 12-6 (0.25 g, 0.327 mmol) and POCl3 (3 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (3 mL), and aqueous ammonia (5 mL) was added at 0 °C, while stirring was continued at room temperature for another 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 40-50% EtOAc in heptane) to give 12-7 (0.15 g, 78%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0282] Step 8. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (107) To a stirred solution of 12-7 (0.15 g, 0.337 mmol) in 1,4 dioxane:HO (4:1, 10 mL) were added (2,5-difluorophenyl)boronic acid (0.8 g, 0.506 mmol) and KPO (0.143 g, 0.674 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (24.7 mg, 0.0337 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite® 545, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography followed by preparative HPLC to give 107 (90 mg, 55.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0283] Example 13. 2-(7-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (110) [ka] Step 1. Synthesis of 1-(5-(benzylthio)-4-methylthiazol-2-yl)-3-(4-bromophenyl)urea (13-1) To a stirred solution of 1-2 (2.5 g, 10.593 mmol) in 1,4-dioxane (25 mL) at 0 °C under an inert atmosphere, 1-bromo-4-isocyanatobenzene (2.08 g, 10.593 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 13-1 (2 g, 44.7%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5) was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ 10.56(br s,1H),9.11(s,1H),7.47(s,4H),7.31-7.20(m,3H),7.11(d,J=6.8Hz,2H),3.87(s,2H),1.86(s,3H)ppm.

[0284] Step 2. Synthesis of 5-(5-(benzylthio)-4-methylthiazol-2-yl)-7-(4-bromophenyl)-5,7-diazaspiro[2.5]octan-6-one (13-2) To a stirred solution of 13-1 (1.5 g, 3.464 mmol) in dry DMF (30 mL) at 0 °C under a nitrogen atmosphere, CsCO (3.37 g, 10.392 mmol) was added portionwise, and the resulting reaction mixture was stirred at room temperature for 30 min. 1,1-bis(bromomethyl)cyclopropane (0.79 g, 3.464 mmol) was added to the reaction mixture at 0 °C, and the reaction mixture was then slowly warmed to room temperature and stirred at 100 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30–40% EtOAc in heptane) to give 13-2 (0.4 g, 23.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS(ESI):C 23 H 22 Calculated for BrN3OS2: 499.04; Found: 500.1 [M+1]. 1 H NMR(400MHz,DMSO-d6):δ 7.58(d,J=7.8Hz,2H),7.32(d,J=8.3Hz,2H),7.28-7.21(m,3H),7.16-7.07(m, 2H),3.93(s,2H),3.85(s,2H),3.59(s,2H),1.91(s,3H),0.80-0.71(m,4H)ppm.

[0285] Step 3. Synthesis of 2-(7-(4-bromophenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (13-3) To a stirred solution of 13-2 (0.1 g, 0.200 mmol) in AcOH / HO (2 mL / 0.2 mL), NCS (0.1 g, 0.751 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (1 mL), and aqueous ammonia (2 mL) was added at 0 °C, while stirring was continued for another 16 hours at the same temperature. The reaction mixture was concentrated to dryness under reduced pressure. The resulting reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash® chromatography (eluted with 1-2% MeOH in DCM) to give 13-3 (0.1 g, 55%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3). 1 H NMR (400MHz, DMSO-d6): δ 7.62-7.54(m,4H),7.34(d,J=7.8Hz,2H),3.98(s,2H),3.62(s,2H),2.41(s,3H),0.78(d,J=6.4Hz,4H)ppm.

[0286] Step 4. Synthesis of 2-(7-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (110) To a stirred solution of 13-3 (90 mg, 0.197 mmol) in 1,4-dioxane and water (2:0.4 mL), (2,5-difluorophenyl)boronic acid (46.74 mg, 0.296 mmol) and KPO (0.10 g, 0.492 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (14 mg, 0.0197 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give 110 (10 mg, 10.3%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3).

[0287] Example 14. 4-Methyl-2-(7-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)thiazole-5-sulfonamide (113) [ka] Step 1. Synthesis of (1-(((4-methylthiazol-2-yl)amino)methyl)cyclopropyl)methanol (14-1) To a stirred solution of 10-1 (3 g, 22.455 mmol) in DMSO (50 mL), compound 2 (3.4 g, 33.682 mmol) was added, followed by K2CO3 (4.65 g, 33.682 mmol), and the reaction mixture was purged under nitrogen for 50 minutes. To the resulting reaction mixture, CuI (0.43 g, 2.245 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 120 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 10–20–70% EtOAc in heptane) to give 14-1 (0.8 g, 18%) as an off-white solid. TLC: 20% EtOAc / heptane (R f :0.5). MS(ESI):C9H 14 Calculated value for N2OS: 198.08; Measured value: 199.1 [M+1] + .

[0288] Step 2. Synthesis of N-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4-methylthiazol-2-amine (14-2) To a stirred solution of 14-1 (0.4 g, 2.020 mmol) in dry DCM (20 mL) at 0 °C under a nitrogen atmosphere, imidazole (0.20 g, 3.030 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 10-15 min. To this reaction mixture, tert-butyldimethylsilyl chloride (0.36 g, 2.424 mmol) was added at 0 °C, and the reaction mixture was then slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 30-40% EtOAc in heptane) to give 14-2 (0.7 g, 55.5%) as a yellow oil. TLC: 30% EtOAc / heptane (R f :0.5).

[0289] Step 3. Synthesis of 3-(4-bromophenyl)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1-(4-methylthiazol-2-yl)urea (14-3) To a stirred solution of 14-2 (0.35 g, 1.121 mmol) in 1,4-dioxane (10 mL) at 0 °C under an inert atmosphere, 1-bromo-4-isocyanatobenzene (0.22 g, 1.121 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 30-40% EtOAc in heptane] to give 14-3 (0.5 g, 43.8%) as an off-white solid. TLC: 20-30% EtOAc / heptane (R f :0.5). MS(ESI):C 22 H 32 Calculated for BrN3O2SSi: 509.12; Found: 512.13 [M+2] + .

[0290] Step 4. Synthesis of 3-(4-bromophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1-(4-methylthiazol-2-yl)urea (14-4) To a stirred solution of 14-3 (0.25 g, 0.490 mmol) in dry THF (5 mL) at 0 °C under a nitrogen atmosphere, tetrabutylammonium fluoride (1 M solution in THF, 1 mL, 0.980 mmol) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold 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 20-30% EtOAc in heptane) to give 14-4 (0.4 g, crude) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS(ESI):C 22 H32 Calculated for BrN3O2SSi: 395.03; Found: 396.1 [M+1] + .

[0291] Step 5. Synthesis of 5-(4-bromophenyl)-7-(4-methylthiazol-2-yl)-5,7-diazaspiro[2.5]octan-6-one (14-5) To a stirred solution of 14-4 (0.2 g, 0.506 mmol) in toluene (5 mL) at 0 °C, triphenylphosphine (0.2 g, 0.759 mmol) was added, followed by DEAD (0.13 g, 0.759 mmol). The resulting reaction mixture was slowly warmed to room temperature and stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 20-30% EtOAc in heptane) to give 14-5 (0.24 g, 63.1%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS(ESI):C 16 H 16 Calculated for BrN3OS: 377.02; Found: 377.90 [M+1] + .

[0292] Step 6. Synthesis of 2-(7-(4-bromophenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonic acid (14-6) To a stirred solution of 14-5 (0.12 g, 0.317 mmol) in dry DCM (10 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.11 g, 0.952 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give 14-6 (0.15 g, crude) as an off-white solid. TLC: 30% EtOAc / heptane (R f: 0.3) was used in the next step without further purification. MS (ESI): C 16 H 16 Calculated for BrN3O4S2: 456.98; Found: 459.7 [M+2] + .

[0293] Step 7. Synthesis of 2-(7-(4-bromophenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (14-7) A mixture of 14-6 (0.15 g, 0.327 mmol) and POCl (1.5 mL) was stirred at 100 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (3 mL) and aqueous ammonia (5 mL) was added at 0 °C, while stirring was continued at room temperature for another 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The solid obtained was filtered off and dried in vacuo to give 14-7 (0.1 g, crude) as a light brown solid. TLC: 30% EtOAc / heptane (R f : 0.3) was used in the next step without further purification. MS (ESI): C 16 H 17 Calculated for BrN4O3S2: 455.99; Found: 458.7 [M+2] + .

[0294] Step 8. Synthesis of 4-methyl-2-(7-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)thiazole-5-sulfonamide (113) To a stirred solution of 14-7 (0.1 g, 0.218 mmol) in 1,4 dioxane:HO (4:1, 10 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75 mg, 0.327 mmol) and NaCO (47 mg, 0.436 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (16 mg, 0.0218 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 100 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography followed by preparative HPLC to give 113 (20 mg, 20%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3).

[0295] Example 15. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N,4-dimethylthiazole-5-sulfonamide (116) [ka] Step 1. Synthesis of 1-(5-(benzylthio)-4-methylthiazol-2-yl)-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (15-1) To a stirred solution of 1-3 (0.5 g, 1.567 mmol) in 1,4-dioxane (5 mL), compound 11-7 (0.46 g, 1.724 mmol), K2CO3 (0.43 g, 3.134 mmol), and 1,2-dimethylethylenediamine (69 mg, 0.783 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (60 mg, 0.313 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50-70% EtOAc in heptane) to give 15-1 (0.25 g, 31.6%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5). MS(ESI):Chemical formula C 27 H 23 Calculated for F2N3OS2: 507.13; Found: 508.44 [M+1] + .

[0296] Step 2. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N,4-dimethylthiazole-5-sulfonamide (116) To a stirred solution of 15-1 (0.15 g, 0.295 mmol) in AcOH:HO (1.5:0.1 mL), NCS (0.15 g, 1.10 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (2 mL), and to this resulting solution, methylamine (33 wt% solution in methanol, 3 mL) was added at 0 °C, and stirring was continued at room temperature for another 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed with water. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 116 (15 mg, 10.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5)

[0297] Example 16. 1-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (139) [ka] Step 1. Synthesis of 4-methyl-5-(methylthio)thiazol-2-amine (16-1) To a stirred solution of 1-1 (1 g, 5.181 mmol) in methanol (10 mL) at 0 °C, sodium thiomethoxide (0.544 g, 7.77 mmol) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in EtOAc, and the organic layer was washed with water. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluting with 10-20% EtOAc in heptane) to give 16-1 (0.6 g, 72.3%) as an off-white solid. TLC: 50% EtOAc / heptane (R f: 0.5). MS (ESI): Calculated for C5H8N2S2: 160.01; Found: 160.75 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.08(br s,2H),2.21(s,3H),2.12(s,3H).

[0298] Step 2. Synthesis of 1-(4-methyl-5-(methylthio)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (16-2) A mixture of 16-1 (0.6 g, 3.75 mmol) and 1-chloro-3-isocyanatopropane (0.58 g, 4.87 mmol) in THF (12 mL) was heated at 65 °C for 5 h. While maintaining the same temperature, TBAI (69 mg, 0.187 mmol) and K2CO3 (0.77 g, 5.62 mmol) were added portionwise to the resulting solution, and stirring was continued at 65 °C for 16 h. 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 (eluted with 60-70% EtOAc in heptane) to give 16-2 (0.5 g, 54.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C9H 13 Calculated for N3OS2: 174.03; Found: 174.77 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ 7.44(s,1H),4.00-3.92(m,2H),3.25-3.17(m,2H),2.29(s,3H),2.28(s,3H),2.00-1.89(m,2H)ppm.

[0299] Step 3. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(methylthio)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (16-3) To a stirred solution of 16-2 (0.5 g, 2.057 mmol) in 1,4-dioxane (6 mL), 11-7 (0.66 g, 2.47 mmol), K2CO3 (0.57 g, 4.11 mmol), and 1,2-dimethylethylenediamine (90 mg, 1.028 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, CuI (78 mg, 0.41 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50-70% EtOAc in heptane) to give 16-3 (0.4 g, 45%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 21 H 19 Calculated for F2N3OS2: 431.09; Found: 432.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.63-7.59(m,2H),7.51-7.34(m,4H),7.30-7.24(m,1H),4.17-4.08(m,2H),3.86-3.78(m,2H),2.34-2.26(m,6H),2.26-2.17(m,2H)ppm.

[0300] Step 4. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (139) To a stirred solution of 16-3 (0.1 g, 0.23 mmol) in ACN:MeOH (2:2 mL) was added ammonium carbamate (0.054 g, 0.69 mmol) and PhI(OAc) (0.34 g, 0.92 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting crude residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 0-70% EtOAc in heptane) followed by preparative HPLC to give 139 (15 mg, 14%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.5).

[0301] Example 17. (R)-1-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (140) and (S)-1-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (141). [ka] Chiral separation of compound 139 under the following conditions gave 140 and 141 as off-white solids.

[0302] 140 chiral separation conditions Chiral HPLC: Rt 14.02 min, 100% Chiral PAK IC (150 × 4.6 mm, 3 μm); Mobile phase A: n-hexane; Mobile phase B: DCM:MEOH (50:50); Program AB 40:60; Flow rate: 1.0 mL / min

[0303] 141 chiral separation conditions Chiral HPLC: Rt 16.02 min, 99.05% Chiral PAK IC (150 × 4.6 mm, 3 μm); Mobile phase A: n-hexane; Mobile phase B: DCM:MEOH (50:50); Program AB 40:60; Flow rate: 1.0 mL / min The stereochemistry of 140 and 141 was arbitrarily assigned.

[0304] Example 18. 1-(2',5'-Difluoro-[1,1'-biphenyl]-4-yl)-3-(5-(isopropylsulfonyl)-4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (162) [ka] Step 1. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (18-1) To a stirred solution of 2-2 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL) were added 4'-bromo-2,5-difluoro-1,1'-biphenyl (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 minutes. 1,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated in a sealed tube at 120 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 18-1 (4.1 g, 41.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 20 H17 Calculated for F2N3OS: 385.11; Measured: 385.90 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.61(d,J=7.8Hz,2H),7.54-7.35(m,4H),7.35-7.21(m,1H),6.70(s,1H),4.1 7(t,J=5.6Hz,2H),3.81(t,J=4.9Hz,2H),2.26(s,3H),2.24-2.21(m,2H)ppm.

[0305] Step 2. Synthesis of 1-(5-bromo-4-methylthiazol-2-yl)-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (18-2) To a stirred solution of 18-1 (1 g, 2.597 mmol) in DCM (10 mL) was added NBS (0.6 g, 3.37 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluted with 30-40% EtOAc in heptane) to give 18-2 (0.7 g, 58.3%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 20 H 16 Calculated for BrF2N3OS: 463.02; Found: 466.0 [M+2] + .

[0306] Step 3. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(5-(isopropylsulfonyl)-4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (162) To a stirred solution of 18-2 (0.5 g, 1.079 mmol) in DMF (10 mL) was added propane-2-sulfinate sodium salt (0.56 g, 4.319 mmol) and CsCO (0.87 g, 2.69 mmol), followed by CuI (21 mg, 0.1079 mmol), followed by L-proline (25 mg, 0.216 mmol). The resulting reaction mixture was heated at 80 °C for 12 h. The reaction mixture was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give 162 (8 mg, 1.5%) as an off-white solid.

[0307] Example 19. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonamide (169) [ka] Step 1. Synthesis of 4-(trifluoromethyl)thiazol-2-amine (19-2) To a stirred solution of 19-1 (2.7 g, 14.210 mmol) in ethanol (50 mL), thiourea (2.16 g, 28.42 mmol) was added, and the resulting reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 20-30% EtOAc in heptane) to give 19-2 (3 g, crude) as a viscous liquid. TLC: 20% EtOAc / heptane (R f : 0.2). MS (ESI): Calculated for C4H3F3N2S: 168.00; Found: 169.00 [M+1] + .

[0308] Step 2. Synthesis of 1-(4-(trifluoromethyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (19-3) To a mixture of 19-2 (4 g, 23.809 mmol) and 1-chloro-3-isocyanatopropane (4.2 g, 35.714 mmol) in THF (60 mL), TBAI (0.38 g, 1.190 mmol) and K2CO3 (4.28 g, 30.951 mmol) were added portionwise, and the resulting reaction mixture was stirred 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 (eluted with 30-40% EtOAc in heptane) to give 19-3 (2.7 g, 45.2%) as an off-white solid. TLC: 40% EtOAc / heptane (R f : 0.5). MS (ESI): Calculated for C8H8F3N3OS: 251.03; Found: 251.80 [M+1] + .

[0309] Step 3. Synthesis of 1-(4-bromophenyl)-3-(4-(trifluoromethyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (19-4) To a stirred solution of 19-3 (2.7 g, 10.756 mmol) in ACN (50 mL) was added 1-bromo-4-iodobenzene (3.65 g, 12.908 mmol), CS2CO3 (6.99 g, 21.512 mmol), followed by CuI (0.81 g, 4.302 mmol), and the resulting reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture, 1,2-dimethylethylenediamine (0.378 g, 4.302 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated in a sealed tube at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 19-4 (2 g, 45.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 14 H 11 Calculated for BrF3N3OS: 404.98; Found: 405.80 [M+1] + .

[0310] Step 4. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonic acid (19-5) To a stirred solution of 19-4 (0.5 g, 1.234 mmol) in dry DCM (8 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.4 mL, 4.938 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 48 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give 19-5 (0.5 g, crude) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3). MS(ESI):C 14 H 11Calculated for BrF3N3O4S2: 484.93; Found: 485.65 [M+1] + .

[0311] Step 5. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonamide (19-6) A stirred solution of 19-5 (0.5 g, 1.030 mmol) in POCl (6 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (3 mL) and aqueous ammonia (6 mL) was added at 0 °C, while stirring was continued at room temperature for another 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give 19-6 (0.2 g, 40.1%) as an off-white solid. MS (ESI): C 14 H 12 Calculated for BrF3N4O3S2: 483.95; Found: 484.85 [M+1] + .

[0312] Step 6. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonamide (169) To a stirred solution of 19-6 (0.2 g, 0.413 mmol) in 1,4 dioxane:HO (5:1 mL) were added (2,5-difluorophenyl)boronic acid (0.1 g, 0.619 mmol) and KPO (0.21 g, 1.032 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (30 mg, 0.041 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 10-30% EtOAc in heptane) to give 169 (25 mg, 11.6%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3).

[0313] Example 20. 2-(3-((2',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (172) [ka] Step 1. Synthesis of 1-(3-bromobenzyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (20-1) To a stirred solution of 2-2 (4 g, 20.304 mmol) in dry THF (80 mL) at 0 °C under a nitrogen atmosphere, NaH (60% w / w in mineral oil, 1.21 g, 30.456 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 30 min. To this reaction mixture, 1-bromo-4-(bromomethyl)benzene (6 g, 24.36 mmol) was added at 0 °C, and the resulting reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (using a gradient method of 50 to 60% EtOAc in heptane) to give 20-1 (5.21 g, 70.3%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 15 H 16 Calculated for BrN3OS: 365.02; Found: 368 [M+2] + . 1 H NMR(400MHz,DMSO-d6):δ 7.51-7.46(m,2H),7.36-7.27(m,2H),6.66(s,1H),4.57(s,2H),4.07(t,J=5.6Hz,2H),3.36-3.33(m,2H),2.23(s,3H),2.06-1.99(m,2H)ppm

[0314] Step 2. Synthesis of 2-(3-(3-bromobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (20-2) To a stirred solution of 20-1 (1 g, 2.739 mmol) in dry DCM (10 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.63 g, 5.48 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5–10 min. The resulting precipitated solid was collected by filtration and dried under vacuum to give 20-2 (1.02 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f : 0.2) was used in the next step without further purification. MS (ESI): C 15 H 16 Calculated for BrN3O4S2: 444.98; Found: 446 [M+1]. 1 H NMR(400MHz,DMSO-d6):δ 7.52-7.45(m,2H),7.35-7.28(m,2H),4.57(s,2H),4.04-3.97(m,2H),3.41-3.25(m,2H),2.32(s,3H),2.08-1.96(m,2H)ppm.

[0315] Step 3. Synthesis of 2-(3-(3-bromobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (20-3) A stirred solution of 20-2 (1 g, 2.242 mmol) in POCl3 (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (5 mL) and aqueous ammonia (10 mL) was added at 0 °C, while stirring was continued at room temperature for another 12 h. 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 (using a gradient method of 1 to 2% MeOH in DCM) to give 20-3 (0.60 g, 60.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 15 H 17Calculated for BrN4O3S2: 443.99; Found: 447.1 [M+2] + . 1 H NMR (400MHz, DMSO-d6): δ 7.55-7.50(m,4H),7.31(s,2H),4.58(s,2H),4.11-4.00(m,2H),3.39-3.33(m,2H),2.42(s,3H),2.10-2.01(m,2H)ppm.

[0316] Step 4. Synthesis of 2-(3-((2',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (172) To a stirred solution of 20-3 (0.3 g, 0.677 mmol) in 1,4-dioxane and water (4:1.5 mL) was added (2,5-difluorophenyl)boronic acid (0.16 g, 1.015 mmol) and KPO (0.36 g, 1.692 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (50 mg, 0.0677 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash® chromatography (eluting with 1-2% MeOH in DCM) to give 172 (0.14 g, 45.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5).

[0317] Example 21. 2-(3-(1-(2',5'-difluoro-[1,1'-biphenyl]-3-yl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (174) [ka] Step 1. Synthesis of 1-(3-bromophenyl)ethan-1-ol (21-2) To a stirred solution of 21-1 (5 g, 25.119 mmol) in methanol (35 mL) at 0 °C under a nitrogen atmosphere, NaBH (1.43 g, 37.68 mmol) was added portionwise, and then the reaction mixture was slowly warmed to room temperature and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting residue was suspended in ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 21-2 (4.5 g, crude) as a yellow sticky solid, which was used in the next step without further purification.

[0318] Step 2. Synthesis of 1-bromo-3-(1-bromoethyl)benzene (21-3) To a stirred solution of 21-2 (4.5 g, 22.38 mmol) in DCM (20 mL) at 0 °C under an inert atmosphere, phosphorus tribromide (2.13 mL, 22.38 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 21-3 (4 g, crude) as a pale green solid, which was used in the next step without further purification. TLC: 10% EtOAc / heptane (R f :0.5).

[0319] Step 3. Synthesis of 1-(1-(3-bromophenyl)ethyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (21-4) To a stirred solution of 2-2 (0.8 g, 4.060 mmol) in dry DMF (8 mL) at 0 °C under a nitrogen atmosphere, NaH (60% w / w in mineral oil, 0.24 g, 6.091 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 15 min. 21-3 (1.6 g, 6.091 mmol) was added to this reaction mixture at 0 °C, and then the reaction mixture was slowly warmed to room temperature and stirred at 50 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 20–30% EtOAc in heptane) to give 21-4 (1.2 g, 77.9%) as a yellow solid. TLC: 40% EtOAc / heptane (R f :0.5). MS(ESI):C 16 H 18 Calculated for BrN3OS: 379.04; Found: 379.9 [M+1] + .

[0320] Step 4. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (21-5) To a stirred solution of 21-4 (1.2 g, 3.165 mmol) in dry DCM (12 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.42 mL, 6.331 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give 21-5 (0.8 g, crude) as a light brown solid. TLC: 50% EtOAc / heptane (R f :0.3). MS(ESI):C 16 H 18 Calculated for BrN3O4S2: 458.99; Found: 461.7 [M+2] + .

[0321] Step 5. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonyl chloride (21-6) A stirred solution of 21-5 (0.8 g, 1.742 mmol) in POCl (8 mL) was stirred for 16 h at 80° C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 21-6 (0.7 g, crude) as an orange solid, which was used without further purification.

[0322] Step 6. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (21-7) To a stirred solution of 21-6 (0.6 g, 1.257 mmol) in THF (6 mL) at 0 °C, aqueous ammonia (1 mL) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred 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 product was purified by CombiFlash® chromatography (eluting with 20-50% EtOAc in heptane) to give the title compound 21-7 (0.16 g, 29.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.3). MS(ESI):C 16 H 19 Calculated for BrN4O3S2: 458.01; Found: 460.7 [M+2] + .

[0323] Step 7. Synthesis of 2-(3-(1-(2',5'-difluoro-[1,1'-biphenyl]-3-yl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (174) To a stirred solution of 21-7 (0.15 g, 0.327 mmol) in 1,4-dioxane and water (2.5:0.5 mL), (2,5-difluorophenyl)boronic acid (0.13 g, 0.818 mmol) and KPO (0.17 g, 0.818 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (25 mg, 0.038 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 10 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 174 (80 mg) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0324] Example 22. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (5) [ka] Step 1. Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (5-2) A mixture of compound 5-1 (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. While maintaining the same temperature, TBAB (1.7 g, 5.263 mmol) and K2CO3 (18.15 g, 131.58 mmol) were added portionwise to the resulting solution, and stirring was 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 (eluted with 60-70% EtOAc in heptane) to give the title compound 5-2 (5.1 g, 49.2%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS(ESI):C8H 11 Calculated value for N3OS: 197.06; Measured value: 198.17 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ 7.30(s,1H),6.60(s,1H),3.99(t,J=5.4Hz,2H),3.20-3.19(m,2H),2.28(s,3H),1.99-1.89(m,2H)ppm.

[0325] Step 2. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (5-3) To a stirred solution of compound 5-2 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL), intermediate No. 5A (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol), followed by CuI (0.96 g, 5.076 mmol) were added, and the resulting reaction mixture was purged under nitrogen for 20 minutes. 1,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated at 120 °C for 24 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give the title compound 5-3 (4.1 g, 41.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS(ESI):C 20 H 17 Calculated for F2N3OS: 385.11; Measured: 385.90 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.61(d,J=7.8Hz,2H),7.54-7.35(m,4H),7.35-7.21(m,1H),6.70(s,1H),4.1 7(t,J=5.6Hz,2H),3.81(t,J=4.9Hz,2H),2.26(s,3H),2.24-2.21(m,2H)ppm.

[0326] Step 3. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (5-4) To a stirred solution of 5-3 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0 °C under 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. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give the title compound 5-4 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2). MS(ESI):C 20 H 17 Calculated for F2N3O4S2: 465.06; Found: 466 [M+1] + .

[0327] Step 4. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (5) A stirred solution of 5-4 (3.3 g, 7.096 mmol) in POCl (33 mL) was stirred at 90° C. for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (66 mL) and aqueous ammonia (33 mL) was added at −5° C., while stirring was continued at room temperature for another 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 100% EtOAc) to give the desired product (1.1 g, 44.6%) as a white solid 5. 1 H NMR(400MHz,DMSO-d6):δ 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,1H),4.17(t, J=6.1Hz,2H),3.82(t,J=5.6Hz,2H),2.45(s,3H),2.29-2.18(m,2H)ppm.

[0328] Step 5. Synthesis of 4'-bromo-2,5-difluoro-1,1'-biphenyl (Intermediate 5A) To a stirred solution of compound 5A (5 g, 17.674 mmol) in 1,4 dioxane:HO (50:5 mL) was added (2,5-difluorophenyl)boronic acid (3.07 g, 19.441 mmol) and KPO (7.5 g, 35.348 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd(dppf)Cl (1.29 g, 1.767 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 100% heptane) to give the title compound Intermediate 5A (2.3 g, 48.6%) as an off-white solid. TLC: 100% heptane (R f :0.5). 1 H NMR (400MHz, CDCl3): δ 7.58(d,J=8.3Hz,2H),7.40(d,J=7.3Hz,2H),7.15-7.06(m,2H),7.05-6.97(m,1H)ppm.

[0329] Example 23. Synthesis of 2-(3-(3'-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (228) [ka] Synthesis of 4-(3-bromo-2,5-difluorophenyl)-1H-pyrazole (23-2) To a stirred solution of 1,3-dibromo-2,5-difluorobenzene (23-1) (1215 mg, 4.47 mmol) and (1H-pyrazol-4-yl)boronic acid (500 mg, 4.47 mmol) in DME (10 mL), water (4.00 mL), KCO (1.853 g, 13.41 mmol) and Pd(dppfcl)DCM (365 mg, 0.447 mmol) were added and purged with nitrogen for 10 minutes. The reaction mixture was heated at 80 °C for 3 hours. The reaction was monitored by UPLC. After completion, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (1×15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator (bath temperature 45° C.) to give 4-(3-bromo-2,5-difluorophenyl)-1H-pyrazole (23-2) (200 mg, 0.749 mmol, 16.7% yield) as a crude compound. LCMS: 1.704 min, 97.65%, 259.0 (M+H). + , (Column: Atlantis dC18 (50 * 4.6) 5 μm), Mobile phase A: 0.1% formic acid in H2O, Mobile phase B: ACN, Flow rate: 1.5 ml / min)

[0330] Synthesis of 4-(3-bromo-2,5-difluorophenyl)-1-(difluoromethyl)-1H-pyrazole (23-3) To a stirred solution of 4-(3-bromo-2,5-difluorophenyl)-1H-pyrazole (23-2) (200 mg, 0.772 mmol) and potassium fluoride (90 mg, 1.544 mmol) in acetonitrile (10 mL), diethyl (bromodifluoromethyl)phosphonate (0.275 mL, 1.544 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (1 × 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator (bath temperature 45 °C) to give the crude product. The resulting crude product was purified by Isolera column chromatography using 230-400 silica gel eluted with 20% ethyl acetate:petroleum ether. Concentrate the combined pure fractions on a rotary evaporator under reduced pressure to obtain pure 4-(3-bromo-2,5-difluorophenyl)-1-(difluoromethyl)-1H-pyrazole (23-3) (20 mg, 0.062 mmol, 8% yield) as a pale yellow liquid. LCMS: 2.044 min, 97.65%, 310.9 (M+H). + (Column: XBridge C18 (50 × 4.6 mm) 3.5 μm, Mobile phase A: 0.1% TFA in H2O, Mobile phase B: ACN, Flow rate: 2.0 ml / min).

[0331] Synthesis of 2-(3-(3'-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (228) To a stirred solution of 4-(3-bromo-2,5-difluorophenyl)-1-(difluoromethyl)-1H-pyrazole (23-3) (20 mg, 0.065 mmol) and 4-methyl-2-(2-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (2-6) (31.0 mg, 0.065 mmol) in THF (10 mL), water (4.00 mL) was added KCO (26.8 mg, 0.194 mmol) and XPhos Pd G (5.09 mg, 6.47 μmol) and purged with nitrogen for 10 minutes. The reaction mixture was heated at 80 °C for 3 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with water (5 mL), followed by brine solution, dried over sodium sulfate, and concentrated. The resulting crude compound was purified by preparative HPLC (Method FA) to give 2-(3-(3′-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2′,5′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (228) (4.25 mg, 7.25 μmol, 11.2% yield) as an off-white solid.

[0332] Example 24: Synthesis of 2-(3-(4-(4,6-difluoropyridin-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (235) [ka] Synthesis of 2-(3-(4-(4,6-difluoropyridin-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (235) To a stirred solution of compound 2-6 (0.18 g, 0.386 mmol) in 1,4-dioxane and water (4:1 mL), 2-bromo-4,6-difluoropyridine (50 mg, 0.257 mmol) was added, followed by KPO (0.10 g, 0.515 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting solution, PdCl(dppf) (19 mg, 0.0257 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound 235 (20 mg, 16.5%) as an off-white solid.

[0333] Example 25: Synthesis of 2-(8-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-7-oxo-2-oxa-6,8-diazaspiro[3.5]nonan-6-yl)-4-methylthiazole-5-sulfonamide (339) [ka] Synthesis of 3-(5-(benzylthio)-4-methylthiazol-2-yl)-1-(4-bromophenyl)-1-((3-(hydroxymethyl)oxetan-3-yl)methyl)urea (25-1) To a stirred solution of compound 13-1 (4 g, 9.259 mmol) in DMF (40 mL) at 0 °C, CS2CO3 (7.54 g, 23.147 mmol) was added, followed by (3-(bromomethyl)oxetan-3-yl)methanol (2.51 g, 13.888 mmol). The resulting reaction mixture was slowly warmed to room temperature and stirred 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 Combi Flash® chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 25-1 (1 g, 20.2%) as a pale yellow solid.

[0334] Synthesis of 6-(5-(benzylthio)-4-methylthiazol-2-yl)-8-(4-bromophenyl)-2-oxa-6,8-diazaspiro[3.5]nonan-7-one (25-2) To a stirred solution of compound 25-1 (0.9 g, 1.70 mmol) in toluene (10 mL) at 0 °C, triphenylphosphine (0.66 g, 2.50 mmol) and DEAD (0.44 g, 2.50 mmol) were added. The resulting reaction mixture was slowly warmed to room temperature and stirred at 100 °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 NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by Combi Flash® chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 25-2 (0.55 g, 63%) as a pale yellow solid.

[0335] Synthesis of 6-(5-(benzylthio)-4-methylthiazol-2-yl)-8-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxa-6,8-diazaspiro[3.5]nonan-7-one (25-3) To a stirred solution of compound 25-2 (0.5 g, 0.968 mmol) in 1,4 dioxane:HO (7:2 mL) was added (2,5-difluorophenyl)boronic acid (0.23 g, 1.45 mmol), followed by KPO (0.4 g, 1.94 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. PdCl(dppf) (35 mg, 0.0484 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by Combi Flash® chromatography (eluting with 50-60% EtOAc in heptane) to give the title compound 25-3 (0.11 g, 21.6%) as an off-white solid.

[0336] Synthesis of 2-(8-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-7-oxo-2-oxa-6,8-diazaspiro[3.5]nonan-6-yl)-4-methylthiazole-5-sulfonamide (339) To a stirred solution of compound 25-3 (0.110 g, 0.200 mmol) in AcOH:HO (3:0.1 mL) was added N-chlorosuccinimide (93 mg, 0.701 mmol), and the reaction mixture was stirred at room temperature for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (1 mL), and aqueous ammonia (2 mL) was added at 0 °C, while stirring was continued at room temperature for another 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and filtered. The resulting crude compound was purified by Combi Flash® chromatography (eluted with 70-80% EtOAc in heptane), followed by preparative HPLC to give the title compound 339 (13 mg, 13%) as an off-white solid.

[0337] Example 26. Synthesis of (S)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-(2-hydroxypropan-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (343) and (R)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-(2-hydroxypropan-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (344) [ka] Synthesis of ethyl (E)-3-ethoxy-2-(ethoxymethyl)acrylate (26-2) To a stirred solution of compound 26-1 (10 g, 68.493 mmol) in toluene (120 mL) at 0 °C under a nitrogen atmosphere, sodium ethoxide (9.3 g, 136.98 mmol) and ethyl formate (10 g, 136.98 mmol) were added, and the resulting reaction mixture was stirred at the same temperature for 2 h. Dimethyl sulfate (13 mL, 136.98 mmol) was added to the reaction mixture at 0 °C, and then the reaction mixture was slowly warmed to room temperature and stirred at 50 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound 26-2 (11 g, crude) as a yellow oil. TLC: 20% EtOAc / heptane (R f :0.2).

[0338] Synthesis of ethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (26-3) To a stirred solution of compound 26-2 (11 g, 54.455 mmol) in ethanol (120 mL) was added urea (3.2 g, 54.455 mmol), followed by concentrated HCl (2.4 mL), and the resulting reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with ethanol. The resulting solid was filtered off and dried in vacuo to give the title compound 26-3 (2.0 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.3) was used in the next step without further purification.

[0339] Synthesis of ethyl 2-oxohexahydropyrimidine-5-carboxylate (26-4) An autoclave was charged with a solution of compound 26-3 (1.6 g, 9.090 mmol) in ethanol (50 mL), and the solution was purged under nitrogen atmosphere for 10 minutes. 10% Pd / C (0.6 g) was added at room temperature under an inert atmosphere. The resulting reaction mixture was stirred at room temperature under 100 Psi of hydrogen for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated to dryness under reduced pressure to give the title compound 26-4 (1.2 g, crude) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0340] Synthesis of ethyl 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxohexahydropyrimidine-5-carboxylate (26-5) To a stirred solution of compound 26-4 (1.2 g, 6.976 mmol) in toluene (20 mL), 4'-bromo-2,5-difluoro-1,1'-biphenyl (1.5 g, 5.581 mmol) and K2CO3 (2.4 g, 17.44 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. XPhos (0.66 g, 1.395 mmol) and Pd2(dba)3 (0.63 g, 0.697 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 60-80% EtOAc in heptane) to give the title compound 26-5 (0.7 g, 28%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0341] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxylate (26-6) To a stirred solution of compound 26-5 (0.7 g, 1.944 mmol) in toluene (12 mL), 2-bromo-4-methylthiazole (0.27 g, 1.555 mmol) and K2CO3 (0.64 g, 4.86 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. XPhos (0.37 g, 0.777 mmol) and Pd2(dba)3 (0.35 g, 0.388 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 10-40% EtOAc in heptane) to give the title compound 26-6 (0.5 g, 62.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0342] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxamide (26-7) A solution of compound 26-6 (0.2 g, 0.437 mmol) in 7 M ammonia in methanol (10 mL) was heated at 70° C. for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluted with 60-80% EtOAc in heptane) to give the title compound 26-7 (0.14 g, 74.8%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0343] Synthesis of 2-(5-carbamoyl-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (26-8) To a stirred solution of compound 26-7 (0.2 g, 0.467 mmol) in dry DCM (5 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (0.1 g, 0.934 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give the title compound 26-8 (0.13 g, crude) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.3) was used in the next step without further purification.

[0344] Synthesis of 2-(5-cyano-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonyl chloride (26-9) To a stirred solution of compound 26-8 (0.1 g, 0.196 mmol) in 1,2-dichloroethane (2 mL), POCl (1 mL) was added, and the resulting reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure to give the title compound 26-9 (0.1 g, crude) as a brown oil. TLC: 70% EtOAc (R f :0.5). This compound was used as is without further purification.

[0345] Synthesis of 2-(5-cyano-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (360) To a stirred solution of compound 26-9 (0.1 g, 0.196 mmol) in THF (2 mL) at 0 °C, aqueous ammonia (1 mL) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 2 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 product was purified by preparative HPLC to give title 360 ​​(15 mg, 15.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0346] Synthesis of methyl 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(methylsulfonyl)thiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxylate (384) To a stirred solution of compound 360 (0.2 g, 0.409 mmol) in MeOH:HO (4:1 mL) was added HSO (2 mL), and the resulting reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluted with 0 to 80% EtOAc in heptane), followed by preparative HPLC to afford title compound 384 (0.15 g, 70.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0347] Synthesis of (R)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-(2-hydroxypropan-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (343) and (R)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-(2-hydroxypropan-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (344) To a stirred solution of compound 384 (0.15 g, 0.287 mmol) in dry THF (5 mL) at -78 °C under an argon atmosphere, methyllithium solution (1.6 M in diethyl ether, 0.89 mL, 1.436 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution 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 (eluted with 0 to 70% EtOAc in heptane) to give 26-10. Preparative HPLC and SFC chiral separation of 26-10 gave compound 343 (0.13 g, 86.6%) and compound 344, respectively, as off-white solids. The stereochemistry was arbitrarily assigned. TLC: 70% EtOAc / heptane (R f :0.5).

[0348] Example 27. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (353) [ka] Synthesis of 5-hydroxytetrahydropyrimidin-2(1H)-one (27-2) To a stirred solution of compound 27-1 (10 g, 111.11 mmol) in 1,5,7-triazabicyclodec-5-ene (0.77 g, 5.555 mmol) at 0° C. in an inert atmosphere, diethyl carbonate (1.57 g, 133.33 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred at 130° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with DCM and stirred for 1 h. The resulting solid was filtered off and dried in vacuo to give the title compound 27-2 (5 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2).

[0349] Synthesis of 5-((tert-butyldiphenylsilyl)oxy)tetrahydropyrimidin-2(1H)-one (27-3) To a stirred solution of compound 27-2 (5 g, 43.103 mmol) in DMF (80 mL) at 0 °C under a nitrogen atmosphere, imidazole (5.8 g, 86.206 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 10-15 min. To this reaction mixture, tert-butyl(chloro)diphenylsilane (17.7 g, 64.654 mmol) was added at 0 °C, and the reaction mixture was then slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 27-3 (10 g, 65.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0350] Synthesis of 5-((tert-butyldimethylsilyl)oxy)-1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-4) To a stirred solution of compound 27-3 (3.7 g, 10.451 mmol) in toluene (10 mL), 2-bromo-4-methylthiazole (1.67 g, 9.406 mmol) was added, followed by K2CO3 (3.6 g, 26.127 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Pd2(dba)3 (0.95 g, 1.045 mmol) and Xphos (0.24 g, 0.522 mmol) were added under a nitrogen atmosphere, and the reaction mixture was heated at 110 °C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluting with 40-50% EtOAc in heptane) to give the title compound 27-4 (1 g, 21.2%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0351] Synthesis of 5-((tert-butyldimethylsilyl)oxy)-1-(4-iodophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-5) To a stirred solution of compound 27-4 (1.0 g, 2.217 mmol) in 1,4-dioxane (15 mL) was added 1-bromo-4-iodobenzene (0.941 g, 3.325 mmol), K2CO3 (0.61 g, 4.434 mmol), and 1,2-dimethylethylenediamine (0.039 g, 0.443 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. To the resulting reaction mixture was added CuI (42 mg, 0.221 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 20-30% EtOAc in heptane) to give the title compound 27-5 (1.0 g, 68.96%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0352] Synthesis of 5-((tert-butyldiphenylsilyl)oxy)-1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-6) To a stirred solution of compound 27-5 (1 g, 1.531 mmol) in 1,4-dioxane and water (15:4 mL), (2,5-difluorophenyl)boronic acid (0.36 g, 2.296 mmol) and KPO (0.811 g, 3.827 mmol) were added, and the reaction mixture was purged under nitrogen for 10 minutes. PdCl(dppf) (0.11 g, 0.153 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 20-30% EtOAc in heptane) to give the title compound 27-6 (0.7 g, 71.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0353] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-hydroxy-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-7) To a stirred solution of compound 27-6 (0.7 g, 1.095 mmol) in dry THF (10 mL) at 0 °C under a nitrogen atmosphere, tetrabutylammonium fluoride (1 M solution in THF, 0.572 mL, 2.190 mmol) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold 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 20-30% EtOAc in heptane) to give the title compound 27-7 (0.4 g, 91.1%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0354] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methoxy-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-8) To a stirred solution of compound 27-7 (0.4 g, 0.997 mmol) in THF (5 mL) at 0 °C under a nitrogen atmosphere, NaH (60% w / w in mineral oil, 79.8 mg, 1.995 mmol) was added portionwise, and the resulting reaction mixture was stirred at the same temperature for 5-10 min. To this reaction mixture, methyl iodide (0.28 g, 1.995 mmol) was added at 0 °C, and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluted with 20-30% EtOAc in heptane) to give the title compound 27-8 (0.2 g, 48.3%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0355] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methoxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (27-9) To a stirred solution of compound 27-8 (0.15 g, 0.361 mmol) in dry DCM (4 mL) at 0 °C under an inert atmosphere, chlorosulfuric acid (84 mg, 0.722 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give the title compound 27-9 (0.15 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.3) was used in the next step without further purification.

[0356] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methoxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (357) A mixture of compound 27-9 (0.15 g, 0.303 mmol) and POCl (2 mL) was stirred at 90 °C for 6 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (1 mL) and aqueous ammonia (2 mL) was added at 0 °C, while stirring was continued at room temperature for another 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound 357 (12 mg, 8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0357] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (353) To a stirred solution of 357 (0.32 g, 0.646 mmol) in DMF (1 mL) at 0° C. under a nitrogen atmosphere, boron tribromide solution (1.0 M in DCM, 10 mL, 10.343 mmol) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred at 100° C. for 48 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 2-5% MeOH in DCM) followed by preparative HPLC to give the title compound 353 (10 mg, 3.2%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3).

[0358] Example 28: Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N-(2-hydroxyethyl)-4-methylthiazole-5-sulfonamide (388) [ka] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (28-1) To a stirred solution of 18-1 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0 °C under 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. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue obtained was purified by trituration with diethyl ether. The resulting solid was filtered off and dried in vacuo to give the title compound 28-1 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2).

[0359] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonyl chloride (28-2) A stirred solution of compound 28-1 (4 g, 8.602 mmol) in POCl (20 mL) was stirred at 100° C. for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure to give the title compound 28-2 (3.5 g, crude) as a brown solid. TLC: 50% EtOAc (R f :0.5). This compound was used directly in the next step without further purification.

[0360] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N-(2-hydroxyethyl)-4-methylthiazole-5-sulfonamide (388) To a stirred solution of compound 28-2 (0.6 g, 1.242 mmol) in THF (6 mL) at 0 °C, DIPEA (0.65 mL, 3.726 mmol) was added, followed by 2-aminoethan-1-ol (0.14 g, 1.863 mmol). The resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluted with 50-60% EtOAc in heptane) followed by preparative HPLC to give the title compound 388 (16 mg, 2.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0361] Example 29: Synthesis of 1-(5-((difluoromethyl)sulfonyl)-4-methylthiazol-2-yl)-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (412) [ka] Synthesis of sodium 2-(3-(2'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfinate (29-2) A stirred solution of sodium sulfite (62.1 mg, 0.483 mmol) in water (10 ml) was stirred at room temperature for 10 minutes. Sodium bicarbonate (83 mg, 0.966 mmol) was added, and the resulting solution was stirred at 50 °C for 1 hour. Compound 29-1 (300 mg, 0.483 mmol) was added in small portions to the solution, and the reaction mixture was continued to stir at 50 °C for 16 hours. After completion of the reaction, as monitored by TLC, the reaction mixture was concentrated in vacuo to remove the solvent. Methanol (5 mL) was added to the residue and stirred for 30 minutes. The formed solid was removed by filtration, and the filtrate was concentrated in vacuo to give the sodium salt of compound 29-2 (300 mg, 90%) as a yellow solid. LCMS: 1.26 min, 66.06%, 433.0[M+H] + (Column: Acquity BEH C18 (50 × 2.1 mm) 1.7 μm), Mobile phase A: 0.1% formic acid in H2O, Mobile phase B: 0.05% formic acid in ACN, Flow rate: 1.0 mL / min NOTE: Sulfonic acid mass was observed by LCMS.

[0362] Synthesis of 1-(5-((difluoromethyl)sulfonyl)-4-methylthiazol-2-yl)-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (412) To a stirred solution of KOH (247 mg, 4.41 mmol) in water (3.00 mL) was added compound 29-2 (100 mg, 0.221 mmol) in acetonitrile (3 mL). The reaction mixture was then cooled to 0-5 °C and vigorously stirred for 10 min. Diethyl (bromodifluoromethyl)phosphonate (177 mg, 0.662 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (Method ABC) to give compound 412 (1.9 mg, 1.8%) as an off-white solid. LCMS: 2.22 min, 98.02%, 482.0(M+H)+ (Column: XBridge C8 (50 × 4.6 mm) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: acetonitrile, Flow rate: 2.0 ml / min) HPLC: 6.86 min, 98.90%, (Column: XBridge C8 (50 x 4.6 mm) 3.5 μm, Mobile phase: A: 5 mM ammonium acetate in H2O, Mobile phase: B: acetonitrile, Flow rate: 2.0 ml / min)

[0363] Example 30: Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(fluoromethyl)thiazole-5-sulfonamide (441) [ka] Synthesis of 1-(4-bromophenyl)-3-(3-chloropropyl)urea (30-2) To a stirred solution of compound 30-1 (5 g, 28.089 mmol) in THF (80 mL) at 0 °C under a nitrogen atmosphere, 1-chloro-3-isocyanatopropane (5 g, 42.134 mmol) was added, and the resulting reaction mixture was slowly warmed to room temperature and stirred at 85 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound 30-2 (6 g, crude) as an off-white solid, which was used in the next step without further purification.

[0364] Synthesis of 1-(4-bromophenyl)tetrahydropyrimidin-2(1H)-one (30-3) To a stirred solution of compound 30-2 (6 g, 20.689 mmol) in acetonitrile (90 mL) was added K2CO3 (5.7 g, 41.379 mmol), followed by TBAB (3.3 g, 10.344 mmol). The resulting reaction mixture was heated at 90 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluted with 70-80% EtOAc in heptane) to give the title compound 30-3 (4 g, 76.9%) as an off-white solid.

[0365] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (30-4) To a stirred solution of compound 30-3 (2.7 g, 11.00 mmol) in 1,4 dioxane:HO (20:5 mL), (2,5-difluorophenyl)boronic acid (2 g, 13.00 mmol) was added, followed by KPO (6.7 g, 32 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. PdCl(dppf) (0.81 g, 1.1 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® column chromatography [eluting with 70-80% EtOAc in heptane] to give the title compound 30-4 (1 g, 33%) as an off-white solid.

[0366] Synthesis of methyl 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylate (30-5) To a stirred solution of compound 30-4 (2 g, 6.937 mmol) in 1,4-dioxane (40 mL), compound 7 (2.31 g, 10.41 mmol) was added, followed by CS2CO3 (5.65 g, 17.34 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (0.4 g, 0.693 mmol) and Pd2(dba)3 (0.6 g, 0.693 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated at 120 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 50 to 100% EtOAc in heptane) to give the title compound 30-5 (1.55 g, 52%) as an off-white solid.

[0367] Synthesis of methyl 5-bromo-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylate (30-6) To a stirred solution of compound 30-5 (1.5 g, 3.50 mmol) in DCM (30 mL) was added N-bromosuccinimide (1.3 g, 7.00 mmol). The resulting reaction mixture was heated at 55 °C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash® chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 30-6 (1.60 g, 90%) as an off-white solid.

[0368] Synthesis of methyl 5-(benzylthio)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylate (30-7) To a stirred solution of compound 30-6 (1.5 g, 3.00 mmol) in 1,4-dioxane (25 mL), phenylmethanethiol (0.92 g, 7.4 mmol) was added, followed by DIPEA (1.2 g, 8.90 mmol), and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (0.18 g, 0.30 mmol) and Pd2(dba)3 (0.14 g, 0.15 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was diluted with water, extracted with EtOAc, and then washed with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by CombiFlash® chromatography (eluting with 60-70% EtOAc in heptane) to give the title compound 30-7 (1.4 g, 86%) as a yellow solid.

[0369] Synthesis of methyl 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-5-sulfamoylthiazole-4-carboxylate (30-8) To a stirred solution of compound 30-7 (1 g, 1.80 mmol) in AcOH:HO (8:0.1 mL) was added N-chlorosuccinimide (0.75 g, 5.40 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (20 mL), and aqueous ammonia (10 mL) was added at 0 °C, while stirring was continued at room temperature for another 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and filtered to give the title compound 30-8 (0.5 g, 54%) as an off-white solid.

[0370] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(hydroxymethyl)thiazole-5-sulfonamide (440) To a stirred solution of compound 30-8 (0.15 g, 0.295 mmol) in THF (4 mL) at 0 °C under a nitrogen atmosphere, lithium borohydride (14 mg, 0.590 mmol) was added. The resulting reaction mixture was stirred at the same temperature for 5-10 minutes, and then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound 440 (10 mg, 7%) as an off-white solid.

[0371] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(fluoromethyl)thiazole-5-sulfonamide (441) To a stirred solution of compound 440 (0.2 g, 0.416 mmol) in DCM (7 mL) at 0 °C under a nitrogen atmosphere, DAST (0.21 g, 1.249 mmol) was added. The resulting reaction mixture was stirred at the same temperature for 5-10 minutes, and then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound 441 (10 mg, 4.9%) as an off-white solid.

[0372] Table 1 shows the structures and analytical data of representative exemplary compounds of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those skilled in the art. [Table 1-1]

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

[0373] Biological Assay Data cell culture Vero cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 100 units / mL of penicillin and streptomycin. Cells were passaged 2–3 times per week to maintain subconfluent density.

[0374] Assay HSV-1 antiviral assay Vero cells, 2.5 x 10 per well 3 Cells were seeded into 96-well plates at a density of 100 μL and allowed to attach overnight. After attachment, the medium was replaced with 50 μL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL of penicillin and streptomycin). Compounds were then added to the cultures using an 8-point, 3-fold serial dilution format using a Tecan D300e digital dispenser. DMSO concentrations were normalized to 0.5% for all treatments. After compound addition, 80 TCID 50 50 μL of infection medium containing HSV-1 was added to the cells and incubated at 37°C for 4 days. After incubation, the plates were equilibrated to room temperature, the medium was removed, and a 1:1 dilution of CellTiterGlo and 60% phosphate-buffered saline was added to the cells. After a 5-minute incubation, cell viability was quantified by measuring brightness using a Tecan Infinite M1000 Pro plate reader.

[0375] HSV-2 antiviral assay Vero cells were added at 1.0 x 10 per well. 4Cells were seeded into 96-well plates at a density of 100 μL and allowed to attach overnight. After attachment, the medium was replaced with 50 μL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL of penicillin and streptomycin). Compounds were then added to the cultures using an 8-point, 3-fold serial dilution format using a Tecan D300e digital dispenser. DMSO concentrations were normalized to 0.5% for all treatments. After compound addition, 160 TCID 50 50 μL of infection medium containing HSV-2 strain G was added to the cells and incubated for 5 days at 37°C. After incubation, 10 μL / well of WST-8 color reagent was added, and the plate was incubated for 3 hours at 37°C. After incubation, cell viability was quantified by measuring absorbance at 460 nm and 620 nm using a Tecan Infinite M 1000 Pro plate reader.

[0376] Table 2 shows assay data for exemplary compounds of the present invention grouped into the following ranges: A = EC 50 B indicates an EC<100 nM, and B indicates an EC<1,000 nM. 50 C indicates an EC of 1,000 nM or greater but less than 5,000 nM. 50 indicates availability, and NA indicates not available. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

[0377] It will be understood that various details of the presently disclosed subject matter may be changed without departing from the scope of the presently disclosed subject matter. Further, the foregoing description is for purposes of illustration only, and not limitation.

[0378] All publications, patents, and patent applications cited herein are hereby incorporated by reference for the teachings to which such citations are applied.

[0379] Test compounds for the experiments described herein were used in free or salt form.

[0380] The specific responses observed may vary according to and depending on the particular active compound selected, or whether a carrier is present, and the type of formulation and mode of administration used, and such expected variations or differences in results are contemplated in accordance with the practice of the present disclosure.

[0381] Although specific embodiments of the present disclosure are illustrated and described in detail herein, the present disclosure is not limited thereto. The above detailed description is provided as an example of the present disclosure and should not be construed as constituting any limitation of the present disclosure. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. Compound of formula I 【Chemistry 161】 or a pharmaceutically acceptable salt thereof, in the formula, 【Chemistry 162】 but, 【Chemistry 163】 And, 【Chemistry 164】 but, 【Chemistry 165-1】 【Chemistry 165-2】 Selected from the group consisting of, X ２ and X ４ However, independently selected from the group consisting of O and S, X ５ However, CH ２ CF ２ , O, S or NR ｙ And, L, 【Chemistry 166】 And, L １ However, is it a combination, or 【Chemistry 167】 but [Chemical 168] When L １ is -CH ２ -, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , and R ｈ However, independently, hydrogen, halo, CN, OH, NR ｎ R ｍ , -C(O)OH, -C(O)OC １－４ Alkyl, -C(O)NR ｎ R ｍ , -SO ２ NR ｎ R ｍ , C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinil, Halo C １－４ Alkyl, hydroxy C １－４ Alkyl and C １－４ Selected from the group consisting of alkoxy groups, or two R groups together with the carbon atom to which they are bonded, C ３－６ Monocycloalkyl, 【Chemistry 169】 Forming a base, R ｎ and R ｍ However, for each of their appearances, independently, hydrogen and C １－４ Selected from the group consisting of alkyl groups, R ｙ However, hydrogen, C １－４ It is alkyl or acetyl, R １ but, 【Chemistry 170】 And, R ２ However, hydrogen, halo, CN, OH, C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinil, Halo C １－４ Alkyl, C １－４ Alkoxy, hydroxy C １－４ Alkyl or Halo C １－４ It is an alkoxy, R ４ However, for each of their appearances, independently, Halo, CN, OH, NR ｎ R ｍ , C １－４ Alkyl, Halo C １－４ Alkyl, C ２－４ Alkenyl, optionally hydroxy C １－３ C substituted with alkyl ２－４ Alkinyl, optionally substituted with halo or cyano, cyclopropyl, and R ４ｂ Selected from the group consisting of, however, one R ４ Only the base is R ４ｂ It could be, R ４ａ However, hydrogen, C １－４ Alkyl, Halo C １－４ Alkyl and hydroxy C １－４ It is alkyl, R ４ｂ but, 【Chemistry 171】 Selected from the group consisting of, R ７ and R ８ However, independently, hydrogen, OH, acetyl, C １－１０ Alkyl, Halo C １－１０ Alkyl, hydroxy C １－１０ Alkyl, C １－４ Alkoxy C １－１０ Alkyl, C ３－６ Selected from the group consisting of monocycloalkyl, phenyl, pyridyl, or indolyl, or R ７ and R ８ However, together with the N atom to which they are bonded, they form an alizidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl group, and the alizidinyl, azetidinyl, pyrrolidinyl, or piperidinyl group is optionally substituted with a halo, CN, or OH. R ７ａ and R ８ａ However, independently, hydrogen, C １－４ Alkyl and C ３－６ Selected from the group consisting of monocycloalkyls, or R ７ and R ８ However, together with the N atom to which they are bonded, they form an alidinyl, azetidinyl, pyrrolidinyl, piperidinylmorpholinyl, or thiomorpholinyl group. R ９ and R ９ａ However, independently, C １－４ Alkyl and Halo C １－４ Selected from the group consisting of alkyl groups, R １０ and R １０ａ However, independently, hydrogen and C １－４ Selected from the group consisting of alkyl groups, R １１ are each independently selected from the group consisting of halo, CN, OH, NR ｎ R ｍ , C １－４ alkyl, halo C １－４ alkyl, C ２－４ alkenyl, C ２－４ alkynyl, and C ３ - ６ monocycloalkyl, R １１ａ is hydrogen, C １－４ alkyl, halo C １－４ alkyl and hydroxy C １－４ alkyl, q and x are independently selected from the group consisting of 0 and 1. w and z are independently selected from the group consisting of 0, 1, and 2. A compound, or a pharmaceutically acceptable salt thereof, in which v and y are independently selected from the group consisting of 0, 1, 2, and 3. 【Request Item 2】 【Chemistry 172】 but, 【Chemistry 173】 And, 【Chemistry 174】 but, 【Chemistry 175】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 3】 【Chemistry 176】 but, 【Chemistry 177】 And, 【Chemistry 178】 but, 【Chemistry 179】 The compound according to claim 2, or a pharmaceutically acceptable salt thereof. 【Request Item 4】 【Chemistry 180】 but, 【Chemistry 181】 And, 【Chemistry 182】 but, 【Chemistry 183】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 5】 【Chemistry 184】 but, 【Chemistry 185】 And, 【Chemistry 186】 but, 【Chemistry 187】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. 【Request Item 6】 【Chemistry 188】 but, 【Chem 189】 And, 【Chemistry 190】 but, 【Chemistry 191】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. L, 【Chemistry 192】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. L, 【Chemistry 193】 The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. L, 【Chemistry 194】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. L, 【Chemistry 195】 The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. R ２ However, H, Cl, F, CH ３ or CF ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ２ However, CH ３ The compound according to claim 11, or a pharmaceutically acceptable salt thereof.

13. R １ but, 【Chemistry 196】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. R １ but, 【Chemistry 197】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. R １ However, R １ but, 【Chemistry 198】 The compound according to claim 14, or a pharmaceutically acceptable salt thereof.

16. R １ but, 【Chemistry 199】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

17. R １ but, 【Chemistry 200】 The compound according to claim 16, or a pharmaceutically acceptable salt thereof.

18. R １ but, 【Chemical Engineering 201】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

19. R １ but, 【Chemical Engineering 202】 The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

20. R １ but, 【Chemical 203】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

21. R １ but, 【Chemical 204】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

22. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a halo for each occurrence, and u is 0, 1, 2, or 3.

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein u is 0.

24. R ４ However, for each of their appearances, independently, halo, CN, methyl, and CHF ２ CF ３ A compound according to claim 1, selected from the group consisting of acetylenyl and cyclopropyl, or a pharmaceutically acceptable salt thereof.

25. R ４ However, for all occurrences, independently selected from the halos, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. ​​A composition for treating or preventing HSV infection in a subject requiring treatment or prevention, comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered to the subject in a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition according to claim 26 for use in a subject requiring treatment or prevention of HSV infection, characterized in that the pharmaceutical composition is administered to the subject in a therapeutically effective amount of the pharmaceutical composition.

29. The composition according to claim 27, wherein the infectious disease is HSV-1 infection.

30. The composition according to claim 27, wherein the infectious disease is HSV-2 infection.

31. A composition for use as a pharmaceutical, comprising a compound described in any one of claims 1 to 25.

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