Cyclic urea thiazolyl compounds for treatment of HSV

Abstract

The present invention provides, in part, cyclic urea thiazolyl compounds and pharmaceutical compositions thereof, and methods of treating and preventing HSV infection.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 401,877 filed on August 29, 2022, U.S. Provisional Application No. 63 / 445,427 filed on February 14, 2023, and U.S. Provisional Application No. 63 / 472,494 filed on June 12, 2023, the contents of which are hereby incorporated herein by reference. Background Art

[0003] Human herpesvirus is a large enveloped double-stranded DNA virus that shares the characteristic of establishing lifelong infection in humans. This is achieved by its ability to be present in the host as an asymptomatic latent infection, wherein the virus is dormant, or after activation as a lytic infection with associated symptoms. These viral infections have been widely prevalent in the world, and it is worth noting that more than 90% of all humans are chronically infected with more than one human herpesvirus.

[0004] Human herpesviruses are classified into three subfamilies (i.e., α, β, and γ) based on their biological properties and the families consist of eight members, i.e., 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 (HHV 6 to 8).

[0005] HSV1 and 2 infection can cause illness in immunocompetent individuals. Both subtypes cause skin genital / anal and oral / nasal (cold sores) lesions, however HSV2 is more common in the former and HSV1 is more common in the latter, making it believed that >80% of genital infections are caused by HSV2. More than 500 million people worldwide suffer from genital herpes infection. Symptoms vary but are usually most severe at the first infection and can last for weeks to months. About 50 to 80% of the population worldwide suffers from oral HSV infection, which is the main cause of cold sores. HSV (and especially HSV1) can also cause lesions on the fingers (whitlows) and other areas of the skin.

[0006] The vast majority of individuals infected with HSV will not experience any noticeable symptoms. However, some will experience repeated outbreaks of infection. In the United States, 20 to 40% of the population will suffer from recurrent HSV lesions on the lips. Notably, oral herpes labialis and whitlow provide a very simple way to spread the virus to other individuals, which can lead to more rare but much more serious HSV-related pathologies. For example, HSV-related eye keratitis is a major cause of blindness. HSV can also cause neonatal encephalitis, which is a life-threatening condition. Other conditions also believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis, and possibly Bell's palsy.

[0007] Primary infection or reactivation of an existing herpes virus infection can be a major cause of illness in immunocompromised individuals. Key high-risk immunocompromised groups include patients undergoing solid organ or stem cell transplantation, individuals with HIV / AIDS, and ICU patients.

[0008] Currently, there is no cure for HSV. Drugs have been developed that can prevent or shorten outbreaks to some extent, but there is still a need for improved therapies to treat HSV infection and inhibit viral replication.

[0009] Currently, nucleotide analogs (e.g. acyclovir and its prodrugs, such as valacyclovir and famciclovir) are used as agents against herpes viruses (e.g. HSV). To exert their effect, these nucleotide analogs must first be phosphorylated by the viral thymidine kinase (TK) and then subsequently converted by cellular kinases into nucleoside triphosphates that inhibit the activity of the viral DNA polymerase. If the virus has no functional active TK, as is the case for, for example, drug-resistant HHV1 mutants or TK-negative viruses, the active substances cannot exert their effect.

[0010] Nucleotide analogs are clinically administered at doses up to hundreds of mg to several grams per day, and even at high doses, and in long treatment durations, these compounds do not completely prevent recurrent outbreaks of symptoms from HSV infection. High doses also lead to elevated levels of adverse reactions.

[0011] Viral shedding is also common in HSV patients and can promote the spread of HSV to more individuals without symptoms. Nucleotide analogs have little effect on addressing this problem and long-term suppressive therapy (e.g., with valacyclovir) has been shown to reduce the risk of transmission by only 46%. Since the nucleotide analogs can be incorporated into the host's genomic DNA via the host DNA polymerase, the mutagenicity of these agents is also a problem, as demonstrated for nucleotide analogs (ganciclovir).

[0012] Given the inadequacy of existing treatments, there is an urgent need to develop improved, well-tolerated anti-herpes therapies.

[0013] One class of compounds being investigated for HSV treatment is helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with novel mechanisms of action for HSV1 and 2. They inhibit the viral heterotrimeric complex composed of helicase, primase, and cofactor subunits with essential functions for viral DNA replication. They are not nucleotide analogs and do not require phosphorylation by TK to inhibit HSV replication and therefore they have potential activity against TK-deficient HSV, which, as described above, is the primary mechanism of resistance to nucleotide analogs (e.g., acyclovir).

[0014] Two examples of helicase-primase inhibitors are BILS-179BS and amenamevir (Katsumata et al., (2018) Biochem Pharm 158, pp. 201-206). BILS-179BS has been administered orally, but early clinical trials were suspended due to adverse events.

[0015] An example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative, and the chemical name is N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide. This compound has been disclosed in WO200053591. WO2001047904 discloses thiazolylamide derivatives and their use as antiviral agents. WO2000053591 discloses thiazolyl derivatives and their utilization as antiviral agents. WO2017174640 discloses aminothiazole derivatives suitable as antiviral agents. WO2019068817 discloses enantiomers of substituted thiazoles as antiviral compounds.

[0016] There remains a need for additional antiviral compounds for the treatment and prevention of HSV infection having an improved profile with respect to safety, potency, selectivity and / or bioavailability. Summary of the invention

[0017] In one embodiment, the present invention provides a compound of formula I,

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0020] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] In another aspect, the present invention 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.

[0022] In another aspect, the present invention provides a method for treating 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.

[0023] In another aspect, the present invention provides a compound of formula II,

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] In another aspect, the present invention 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.

[0028] In another aspect, the present invention provides a method for treating 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

[0029] FDA-approved nucleoside drugs (acyclovir and its prodrug valacyclovir) have been the mainstay of HSV treatment for many years. For more than two decades, there have been no regulatory-approved small molecule drugs for the treatment of HSV, making it an area of ​​significant unmet medical need.

[0030] Prelivir has entered the Phase III clinical development stage for the treatment of HSV by AiCuris. Bayer has applied for two patent applications for Prelivir-related structures. The first application WO200053591 (filed on February 24, 2000) relates to compounds with an acyclic urea core. The second application WO2001047904 (filed on December 12, 2000) relates to compounds with an acyclic amide core, including Prelivir. The discovery of Prelivir (BAY 57-1293) is summarized in G. Kleymann, "Discovery, SAR and Medicinal Chemistry of Herpesvirus Helicase Primase Inhibitors", Curr. Med. Chem.-Anti-Infective Agents, 2004, 3, 69-83.

[0031] Of the 227 exemplary acyclic urea compounds disclosed in WO200053591, in vitro HSV-1 and HSV-2 bioassay data are provided for only four examples: 43, 123, 94, and 2. The structures of Examples 123 and 152 are shown below:

[0032]

[0033] Likewise, of the 132 exemplary acyclic amide compounds disclosed in WO2001047904, in vitro HSV-1 and HSV-2 bioassay data are provided for only seven examples: 14, 57, 8, 23, 38, 87, and 126. The structures of Examples 87 and 38 are shown below:

[0034]

[0035] Example 5 described herein is a preferred compound of the present invention. Its solubility in water at ∼pH 7.0 (measured at room temperature) is less than 5 μg / ml. Animal studies were conducted to determine the half-life and clearance of Example 5. In rats, dogs, monkeys, and minipigs, solutions of the compound were administered intravenously at doses of 0.2 mg / kg, 0.15 mg / kg, 0.2 mg / kg, and 0.25 mg / kg, respectively, resulting in the terminal half-life and clearance shown in the following table:

[0036] Species Half-life (days) Clearance (L / hr / kg) Rat 0.8 0.02 dog 2.3 0.002 monkey 3.0 0.004 Mini Pig 5.6 0.0018

[0037] Based on the above pharmacokinetic data in multiple species, and using allometric scaling, the compound has a predicted human terminal biological half-life of 7.6 days (182 hours) and a clearance of 0.06 L / hr.

[0038] Table 1 shows comparative bioassay data for Example 5 of the present invention and the four prior art compounds shown above, which lack substituents on the urea nitrogen atom between the carbonyl and phenyl moieties (acyclic ureas) or lack substituents on the carbon atom between the carbonyl and phenyl moieties (acyclic amides). The prior art compounds were prepared according to known procedures and all bioassay data presented in Table 1 were obtained using the bioassays described herein.

[0039] Table 1: Comparison of biological activities of Example 5 with acyclic urea and amide compounds in the prior art

[0040]

[0041] The cyclic urea compounds of the present invention incorporate two novel structural changes that are lacking in these prior art compounds. First, both nitrogen atoms have been covalently bonded to carbon atoms making them tetrasubstituted ureas. Second, the N-alkyl groups attached to the nitrogen atoms are connected to form a ring. These features are not taught or suggested in the Bayer patents mentioned above.

[0042] Only one acyclic urea compound (Example 38) in WO200053591 features a tetrasubstituted core ring (i.e., a core ring having substituents attached to two urea nitrogen atoms). More specifically, while all exemplary compounds are substituted with a diverse group of substituents on the nitrogen bearing the thiazole heterocycle, only Example 38 is additionally substituted on the opposite urea nitrogen atom. Likewise, only one compound (Example 45) in WO2001047904 has a substituent on the benzyl carbon atom next to the amide carbonyl, while a diverse group of substituents is present on the amide nitrogen.

[0043]

[0044] No biological data is provided for any of these compounds and there is no teaching, suggestion or motivation to cyclize the urea moiety as exemplified in WO200053591 or WO2001047904. However, applicants have discovered that the novel cyclic urea compounds described herein (particularly tetrahydropyrimidin-2(1H)-ones) are surprisingly active relative to their acyclic counterparts and possess different physical and biological properties.

[0045] Since biological data for Examples 38 and 45 discussed above are not provided in the prior art, Applicants prepared a novel acyclic tetrasubstituted urea Reference Compound A for direct comparison of biological activity relative to Example 5. Applicants note that direct comparison with Example 38 of WO200053591 may lead to ambiguous results due to the presence of a methyl ester moiety on the terminal phenyl group.

[0046]

[0047] As shown in Table 2, Reference Compound A was 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 noted that Reference Compound A was 50-fold less active in the HSV-1 assay and 54-fold less active in the HSV-2 assay compared to the acyclic amide analog Example 87 shown above.

[0048] Table 2: Comparison of biological activities of Example 5 of the present invention and novel acyclic analogs substituted on BOTH urea nitrogen atoms

[0049] Compound Core part HSV-1EC50(nM) HSV-2EC50(nM) Example 5 Cyclic urea 19 10 Reference Compound A Acyclic urea 844 925

[0050] Without specific teachings in the prior art, it is not possible to predict a priori the effect of alkylation of the urea nitrogen atom between the urea carbonyl and the phenyl group (as in reference compound A) on activity. The comparative data presented above demonstrate that the biological activity of the acyclic tetrasubstituted urea is significantly reduced. In the absence of structural information showing how the compound binds to the target, it is not possible to know why methylation reduces activity. There are a number of hypotheses that could explain this observation. Without wishing to be bound by theory, these include the following: 1) if the urea NH forms an H-bond with the target, then methylation will remove the NH that contributes the H-bond; 2) there may not be enough space in the target to accommodate a methyl group; 3) if the urea carbonyl forms an H-bond with the target, then methylation may sterically interfere and weaken the interaction; 4) methylation may change the conformational dynamics of the urea, limiting its ability to form a favorable bond conformation; 5) methylation will change the physical properties of the molecule, which may reduce its propensity to partition into an inhibitor binding pocket; and 6) methylation will change the physical properties of the molecule, which may reduce its ability to enter a cell or, once inside the cell, enter the target. Therefore, the behavior observed for Example 5, in which biological activity was significantly increased by cyclizing the urea moiety, can be considered unexpected and surprising from a medicinal chemistry perspective.

[0051] Applicants further note that generally in medicinal chemistry, cyclization of acyclic moieties results in reduced activity because rotational freedom is limited to one conformer, which is statistically unlikely to be the preferred conformation at the binding site. Without wishing to be bound by theory, additional potential explanations for the surprising results presented herein include (but are not limited to):

[0052] 1. Conformational preference: Cyclization of compound 5 may lead to a specific conformation that is more favorably aligned with the target binding site, allowing for stronger interactions and increased biological activity. This preferred conformation may enhance binding affinity and potency.

[0053] 2. Structural rigidity: The cyclic form of compound 5 may exhibit greater structural rigidity, leading to improved stability and reduced entropic cost of binding. This may promote more optimized binding geometry and enhance target engagement.

[0054] 3. Steric confinement: Cyclization allows the compound to adopt a three-dimensional shape that is complementary to the binding pocket of the target, leading to improved molecular recognition and enhanced biological activity.

[0055] Applicants have further discovered that in the novel cyclic ureas of the present invention, the 6-membered core ring (i.e., tetrahydro-2(1H)-pyrimidinone) is generally more active than the corresponding 5-membered core ring (i.e., 2-imidazolidinone). Consider the following two groups of compounds: Example 5 / 104 and Example 259 / 324 having the following structures:

[0056]

[0057]

[0058] As shown in Table 3, in the HSV-1 assay, Example 5 was 91 times more active than Example 104 (5-membered ring analog) and >200 times more active in the HSV-2 assay. Similarly, Example 259 was 4 times more active than Example 314 (5-membered ring analog).

[0059] Table 3: Comparison of biological activities of compounds with 5- and 6-membered ring urea cores

[0060] Compound Core ring size HSV-1EC50(nM) HSV-2EC50(nM) Example 5 6 member ring 19 10 Example 104 5 member ring 1740 >2000>2 Example 259 6 member ring 10 7 Example 314 5 member ring Not tested 28

[0061] The specific reasons behind this trend remain unknown and will require detailed determination of compound-target interactions, including potential differences in conformational flexibility, binding affinity, and steric effects. Without wishing to be bound by theory, the larger size of the 6-membered core ring compared to the 5-membered core ring may contribute to improved binding interactions and enhanced potency, which may be a result of the increased conformational space accessible to the 6-membered ring.

[0062] The features and other details of the present invention will now be described in more detail. Before further describing the present invention, certain terms used in this specification, examples and appended claims are collected here. These definitions should be read in light of the rest of the present invention and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art.

[0063] definition

[0064] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched chain hydrocarbons of 1 to 6 or 1 to 4 carbon atoms, referred to herein as C1-6 Alkyl and C 1-4 Alkyl. Examples include, but are 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, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0065] The term "alkylene" as used herein refers to a diradical alkyl group.

[0066] As used herein, the term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to herein as C 2-6 Examples include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0067] As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2 to 6 carbon atoms, referred to herein as C 2-6 Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0068] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached to an oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1 to 6 or 1 to 4 carbon atoms, referred to herein as C 1-6 Alkoxy and C 1-4 Alkoxy. Examples include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0069] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. Exemplary alkoxyalkyl groups include, but are not limited to, C 1-3 Alkoxy or C 1-4 Alkoxy substituted C 1-6 Alkyl groups are referred to herein as C 1-3 Alkoxy C 1-6 Alkyl and C 1-4 Alkoxy C 1-6 Alkyl. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0070] The term "cyano" as used herein refers to CN.

[0071] As used herein, the term "monocyclic alkyl" refers to a saturated monocyclic hydrocarbon group of, for example, 3 to 6 carbon atoms, referred to herein as C 3-6 Examples include, but are not limited to, cyclooctyl, cycloheptyl, cyclohexyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

[0072] As used herein, the term "halo" or "halogen" refers to F, Cl, Br or I.

[0073] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups include, but are not limited to, C 1-6 Alkyl or C 1-4 Alkyl, referred to herein as halo 1-6 Alkyl and halogen C 1-4 Alkyl. For example, halo 1-6 Alkyl refers to a straight or branched chain alkyl group of 1 to 6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, -CF3, CF3CH2-, CH3CF2-, CF3CCl2-, and CF3CF2-.

[0074] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Exemplary alkoxy groups include, but are not limited to, C 1-6 Alkoxy or C 1-4 Alkoxy, referred to herein as halo 1-6 Alkoxy and halogen C 1-4 Alkoxy. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O-CF3CH2O-, and CF3CF2O-.

[0075] As used herein, the terms "hydroxy" and "hydroxyl" refer to OH.

[0076] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, C 1-6 Alkyl or C 1-4 Alkyl, referred to herein as hydroxyl C 1-6 Alkyl and hydroxyl C 1-4 Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, (CH3)2C(OH)CH2-, and HOCH2CH(OH)CH2-.

[0077] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups. Exemplary hydroxyalkoxy groups include, but are not limited to, C 1-6 Alkoxy or C 1-4 Alkoxy, referred to herein as hydroxyl C 1-6 Alkoxy and hydroxyl C 1-4 Alkoxy. Examples include, but are not limited to, HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, (CH3)2C(OH)CH2O-, and HOCH2CH(OH)CH2O-.

[0078] As used herein, the term "R n R m N-alkyl-" refers to n R m N-(as defined herein) substituted alkyl. n R m N-alkyl-groups include, but are not limited to, n R m N-substituted C 1-6 Alkyl or C 1-4 Alkyl groups, referred to herein as R n R m NC 1-6 Alkyl and R n R m NC 1-4 Alkyl. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2-, and CH3CH(NH2)CH2-.

[0079] As used herein, the term "R n R m N-alkoxy" refers to n R m N-(as defined herein) substituted alkoxy. n R m N-alkoxy includes but is not limited to n R m N-substituted C 1-6 Alkoxy or C 1-4 Alkoxy, referred to herein as R n R m NC 1-6 Alkoxy and R n R m NC 1-4Alkoxy. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0080] As used herein, when a bicyclic ring is shown to have a floating point of attachment and / or floating substituents, e.g., as in In this context, it means that the bicyclic ring may be connected via a carbon atom on any ring, and the substituents (e.g., R 33 The groups) may be independently attached to either ring or both rings.

[0081] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the invention 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 (e.g., dogs, cats, and the like), farm animals (e.g., dairy cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). It is contemplated that the mammals treated in the methods of the invention are mammals requiring treatment for HSV infection.

[0082] The term "modulate" includes antagonism (eg, inhibition), agonism, partial antagonism, and / or partial agonism.

[0083] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans as appropriate. For human administration, preparations should meet sterility, pyrogenicity and general safety and purity standards as required by the FDA Office of Biologics standards.

[0084] 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 these media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional or enhanced therapeutic functions.

[0085] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0086] As used herein, the term "pharmaceutically acceptable salt" refers to salts having acidic or basic groups which may be present in the compounds used in the compositions. The compounds included in the compositions of the present invention that are basic in nature can form a wide range of salts with various inorganic and organic acids. Acids useful in preparing pharmaceutically acceptable acid addition salts of these basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically 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, gentisate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, pyroglutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). The compounds included in the compositions of the present invention that are acidic in nature can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, octyl, potassium and iron salts. The compounds comprising a basic or acidic moiety included in the compositions of the present invention may also form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compounds may exist in the form of acid addition salts, zwitterions or base salts.

[0087] As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, or animal (e.g., mammal or human) that the researcher, veterinarian, physician, or other clinician is seeking. The compounds or pharmaceutical compositions of the present invention are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventive effect.

[0088] The term "treating" includes any effect resulting in an improvement of the disease, for example, alleviating, reducing, moderating or eliminating the viral infection.

[0089] The compounds of the present invention may contain one or more chiral centers and therefore exist as stereoisomers. When the term "stereoisomer" is used herein, it 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, but the skilled artisan will recognize that the structure may implicitly indicate a chiral center. The present invention includes various stereoisomers of these compounds and mixtures thereof. A mixture of enantiomers or diastereomers may be designated by nomenclature as "(±)", but the skilled artisan will recognize that the structure may implicitly indicate a chiral center.

[0090] The compounds of the present invention may contain one or more double bonds and therefore exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bond. "Z" refers to a bond that can be a single bond, a double bond, or a triple bond as described herein. Substituents around a carbon-carbon double bond are designated as "Z" or "E" configurations, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds include both "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" means that the substituents are located on the same side of the double bond and "trans" means that the substituents are located on the opposite side of the double bond.

[0091] The compounds of the present invention may contain carbocyclic or heterocyclic rings and therefore exist in the form of geometric isomers resulting from the arrangement of substituents around the rings. The arrangement of substituents around carbocyclic or heterocyclic rings is designated as "Z" or "E" configuration, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings include both "Z" and "E" isomers. Substituents around carbocyclic or heterocyclic rings may also be referred to as "cis" or "trans", wherein the term "cis" indicates that the substituents are located on the same side of the ring plane and the term "trans" indicates that the substituents are located on the opposite side of the ring plane. A mixture of compounds in which the substituents are arranged on the same side and the opposite side of the ring plane is designated as "cis / trans".

[0092] Individual enantiomers and diastereomers of the compounds of the invention may be synthesized from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those of ordinary skill. These resolution methods are exemplified by (1) coupling a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation 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 may also be resolved into their component enantiomers by well-known methods such as chiral phase liquid chromatography or crystallization of the compounds in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the conversion of a pre-existing stereocenter, is well known in the art. Stereoselective synthesis includes both enantio- and diastereoselective conversions and may involve the use of chiral auxiliary agents. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0093] The compounds disclosed herein may exist in solvated and unsolvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, and the like), and it is contemplated that the present invention encompasses 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 crystalline form.

[0094] The present invention also encompasses isotopically labeled compounds of the present invention which are identical to those recited herein except that one or more atoms are replaced by an atom having an atomic mass or mass number which is different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. For example, the compounds of the invention may have one or more H atoms replaced by deuterium.

[0095] Certain isotopically labeled compounds disclosed herein (e.g., those labeled with 3 H and 14 C-labeled) are suitable for use in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0096] The term "prodrug" refers to a compound that is converted in vivo to produce a compound disclosed herein or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The conversion can occur in various locations (e.g., in the intestinal lumen or during transport in the intestine, blood or liver) by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidation and or reduction metabolism). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0097] Cyclic urea thiazole compounds

[0098] In one aspect, the present invention provides a compound of formula I,

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein:

[0101] Select from the group consisting of:

[0102]

[0104] Select from the group consisting of:

[0105]

[0107] X is CR 2 or N;

[0108] X 0 O, S or NR x ;

[0109] X 1 , X 2 , X 3 , X 4 and X 6 independently selected from the group consisting of O and S;

[0110] X 5 is CH2, CF2, O, S or NR y ,

[0111] L is

[0113] L 1 is a key; or when yes When L 1 is -CH2- or CH(CH3)-;

[0114] L 2 is -CH2-, -CH2CH2- or -CH2CH2CH2-;

[0115] R a , R b , R c , R d , R e , R f , R g , R h , R i and R j are independently selected from the group consisting of: hydrogen, halide, 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, halogen C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and R 13 , the restriction condition is R a , R b , R c , R d , R e , R f , R g , R h , R i and R j Only one of them can be R13 ; or two R groups together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Group;

[0116] R x and R y independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and acetyl groups;

[0117] R 1 yes

[0118] R 2 is hydrogen, halogen, C 1-4 Alkyl, halogen C 1-4 Alkyl, C 1-4 Alkoxy or halogen C 1-4 Alkoxy;

[0119] R 3 Each occurrence is independently selected from the group consisting of halo and cyano;

[0120] R 3a , R 4a , R 11a , R 12a and R 14a independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl and hydroxyl C 1-4 alkyl;

[0121] R 4 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, optionally through hydroxyl C 1-3 Alkyl substituted C 2-4 alkynyl, cyclopropyl optionally substituted by halogen or cyano, and R 4b , the constraint is that there is only one R 4 The group can be R 4b ;

[0122] R 4b Select from the group consisting of:

[0123]

[0124] R 7 and R 8independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, acetyl, C 3-6 Monocyclic alkyl, phenyl and pyridyl; or R 7 and R 8 Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group;

[0125] R 7a and R 8a independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Monocyclic alkyl, or R 7a and R 8a Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl, morpholinyl or thiomorpholinyl group;

[0126] R 9 and R 9a Independently selected from C 1-4 Alkyl and halogen C 1-4 The group consisting of alkyl groups;

[0127] R 10 and R 10a independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0128] R 11 , R 12 and R 14 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and cyclopropyl;

[0129] R 13 Select from the group consisting of:

[0131] R n and R m Each occurrence is independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0132] j, p, q, r and x are independently selected from the group consisting of 0 and 1;

[0133] k, n, s, w and z are independently selected from the group consisting of 0, 1 and 2; and

[0134] m, t, u, v and y are independently selected from the group consisting of 0, 1, 2 and 3.

[0135] In another aspect, the present invention provides a compound of formula Ia,

[0136]

[0137] or a pharmaceutically acceptable salt thereof, wherein:

[0138] yes

[0139] yes

[0140] X is CR 2 or N;

[0141] X 5 is CH2, CF2, O, S or NR y ;

[0142] L is

[0143] R a , R b , R c , R d , R e , R f , R g and R h are independently selected from the group consisting of: hydrogen, halide, 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, halogen C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and R 13 , the restriction condition is R a , R b , R c , R d , R e , R f , R g and R h Only one of them can be R 13; or two R groups together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Group;

[0144] R y It is hydrogen, C 1-4 Alkyl or acetyl;

[0145] R 1 yes

[0146] R 2 is hydrogen, halogen, C 1-4 Alkyl, halogen C 1-4 Alkyl, C 1-4 Alkoxy or halogen C 1-4 Alkoxy;

[0147] R 3 Each occurrence is independently selected from the group consisting of halo and cyano;

[0148] R 4 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, optionally through hydroxyl C 1-3 Alkyl substituted C 2-4 alkynyl and cyclopropyl which may be substituted with halogen or cyano;

[0149] R 7 and R 8 independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, acetyl, C 3-6 Monocyclic alkyl, phenyl and pyridyl; or R 7 and R 8 Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group;

[0150] R 7a and R 8a independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Monocyclic alkyl, or R 7a and R 8a Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl, morpholinyl or thiomorpholinyl group;

[0151] R 9 and R 9aIndependently selected from C 1-4 Alkyl and halogen C 1-4 The group consisting of alkyl groups;

[0152] R 10 and R 10a independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0153] R 13 Select from the group consisting of:

[0154] R 14 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and cyclopropyl;

[0155] R 14a Selected from the group consisting of: hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl and hydroxyl C 1-4 alkyl;

[0156] R n and R m Each occurrence is independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0157] j is selected from the group consisting of 0 and 1;

[0158] k is selected from the group consisting of 0, 1, and 2; and

[0159] m, u and v are independently selected from the group consisting of 0, 1, 2 and 3.

[0160] The following examples further describe a compound of Formula I, Formula Ia, or a pharmaceutically acceptable salt thereof. It will be recognized that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the invention.

[0161] In certain embodiments, yes

[0162] In certain embodiments, yes

[0163] In certain embodiments, yes

[0164] In certain embodiments, yes

[0165] In certain embodiments, Select from the group consisting of:

[0166]

[0167] In certain embodiments, Select from the group consisting of:

[0168]

[0169] In certain embodiments, Select from the group consisting of:

[0170]

[0171] In certain embodiments, yes

[0172] In certain embodiments, yes

[0173] In certain embodiments, yes

[0174] In certain embodiments, yes

[0175] In certain embodiments, Select from the group consisting of:

[0176]

[0177] In certain embodiments, Select from the group consisting of:

[0178]

[0179] In certain embodiments, Select from the group consisting of:

[0180]

[0181] In certain embodiments, L is

[0182] In certain embodiments, L is

[0183] In certain embodiments, L is

[0184] In certain embodiments, L is

[0185] In certain embodiments, L is

[0186] In certain embodiments, L is

[0187] In certain embodiments, L is

[0188] In certain embodiments, L is

[0189] In certain embodiments, X is CR 2 .

[0190] In certain embodiments, X is CR 2 and R 2 It is Cl, F, CH3 or CF3.

[0191] In certain embodiments, X is CR 2 and R 2 It is CH3.

[0192] In certain embodiments, R 1 yes

[0193] In certain embodiments, R 1 yes

[0194] In certain embodiments, R 1 yes

[0195] In certain embodiments, R 1 yes

[0196] In certain embodiments, R 1 yes

[0197] In certain embodiments, R 1 yes

[0198] In certain embodiments, R 1 yes

[0199] In certain embodiments, R 1 yes

[0200] In certain embodiments, R 1 yes

[0201] In certain embodiments, R 1 yes

[0202] In certain embodiments, R 3 Each occurrence is halo and u is 1, 2 or 3.

[0203] In certain embodiments, R 3 Each occurrence is F and u is 1, 2 or 3.

[0204] In certain embodiments, R 4 Each occurrence is independently selected from the group consisting of halo, CN, methyl, CHF2, CF3, ethynyl, and cyclopropyl.

[0205] In certain embodiments, R 4 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NH2, NH(CH3), N(CH3)2, C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, optionally through hydroxyl C 1-3 Alkyl substituted C 2-4 alkynyl and cyclopropyl which may be substituted with halogen or cyano.

[0206] In certain embodiments, R 4b Select from the group consisting of:

[0207]

[0208] In certain embodiments, R 4b Select from the group consisting of:

[0209]

[0210] In certain embodiments, R a , R b , R c , R d , R e , R f , R g , R h , R i and R jindependently selected from the group consisting of: hydrogen, halide, 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, halogen C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 Alkoxy.

[0211] In certain embodiments, R 13 Select from the group consisting of:

[0212]

[0213] In certain embodiments, R 13 Select from the group consisting of:

[0214]

[0215] In another aspect, the present invention provides a compound of formula II,

[0216]

[0217] or a pharmaceutically acceptable salt thereof, wherein: yes Select from the group consisting of:

[0218]

[0220] X 2 and X 4 independently selected from the group consisting of O and S;

[0221] X 5 is CH2, CF2, O, S or NR y ,

[0222] L is

[0223] L 1 is a key; or when yes When L 1 is -CH2-;

[0224] R a , R b , R c , Rd , R e , R f , R g and R h independently selected from the group consisting of hydrogen, halogen, 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, C 2-4 Alkynyl, halide C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 Alkoxy; or two R groups together with the carbon atom to which they are attached form a C 3-6 Monocyclic alkyl, Group;

[0225] R n and R m Each occurrence is independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0226] R y It is hydrogen, C 1-4 Alkyl or acetyl;

[0227] R 1 yes

[0228] R 2 is hydrogen, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halide C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl or halogen C 1-4 Alkoxy;

[0229] R 4 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, optionally through hydroxyl C 1-3 Alkyl substituted C 2-4 alkynyl, cyclopropyl optionally substituted by halogen or cyano, and R4b , the constraint is that there is only one R 4 The group can be R 4b ;

[0230] R 4a It is hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl and hydroxyl C 1-4 alkyl;

[0231] R 4b Select from the group consisting of:

[0232]

[0234] R 7 and R 8 are independently selected from the group consisting of: hydrogen, OH, acetyl, C 1-10 Alkyl, halogen C 1-10 Alkyl, hydroxyl C 1-10 Alkyl, C 1-4 Alkoxy C 1-10 Alkyl, C 3-6 monocyclic alkyl, phenyl, pyridyl or indolyl; or R 7 and R 8 together with the N atom to which it is attached, forms an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl, wherein the aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with halo, CN or OH;

[0235] R 7a and R 8a independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Monocyclic alkyl, or R 7a and R 8a Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl, morpholinyl or thiomorpholinyl group;

[0236] R 9 and R 9a Independently selected from C 1-4 Alkyl and halogen C 1-4 The group consisting of alkyl groups;

[0237] R 10 and R 10a independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0238] R 11 Independently selected from the group consisting of: halogen, CN, OH, NRn R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 Monocyclic alkyl;

[0239] R 11a It is hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl and hydroxyl C 1-4 alkyl;

[0240] q and x are independently selected from the group consisting of 0 and 1;

[0241] w and z are independently selected from the group consisting of 0, 1 and 2; and

[0242] v and y are independently selected from the group consisting of 0, 1, 2 and 3.

[0243] The following examples further describe a compound of Formula II or a pharmaceutically acceptable salt thereof. It will be recognized that all chemically permissible combinations of the embodiments described herein are contemplated as further embodiments of the invention.

[0244] In certain embodiments:

[0245] yes

[0246] Select from the group consisting of:

[0247] In certain embodiments:

[0248] yes

[0249] yes

[0250] In certain embodiments:

[0251] yes

[0252] Select from the group consisting of:

[0253] In certain embodiments:

[0254] yes

[0255] Select from the group consisting of:

[0256] In certain embodiments:

[0257] yes

[0258] yes

[0259] In certain embodiments: L is

[0260] In certain embodiments, L is

[0261] In certain embodiments, L is

[0262] In certain embodiments: L is

[0263] In certain embodiments, L is

[0264] In certain embodiments: R 2 It is H, Cl, F, CH3 or CF3.

[0265] In certain embodiments: R 2 It is CH3.

[0266] In certain embodiments:

[0267] R 1 yes

[0268] In certain embodiments: R 1 yes

[0269] In certain embodiments: R 1 yes

[0270] In certain embodiments: R 1 yes

[0271] In certain embodiments: R 1 yes

[0272] In certain embodiments: R 1 yes

[0273] In certain embodiments: R 1 yes

[0274] In certain embodiments: R 1 yes

[0275] In certain embodiments: R 1 yes

[0276] In certain embodiments: R 3 Each occurrence is halo and u is 0, 1, 2 or 3.

[0277] In some embodiments: u is 0.

[0278] In certain embodiments: R 4 Each occurrence is independently selected from the group consisting of halo, CN, methyl, CHF2, CF3, ethynyl, and cyclopropyl.

[0279] In certain embodiments: R 4 Each occurrence is independently selected from halo.

[0280] How to use

[0281] The compounds according to the invention are suitable for the treatment and prevention of disorders caused by herpes viruses, in particular herpes simplex viruses.

[0282] In one aspect, the present invention provides a method for treating or preventing HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the infection is a herpes simplex infection.

[0284] In some embodiments, the infection is an HSV-1 infection.

[0285] In some embodiments, the infection is an HSV-2 infection.

[0286] In some embodiments, the infection is a herpes simplex infection and the subject displays symptoms such as herpes labialis, genital herpes, HSV-related keratitis, encephalitis, or pneumonia.

[0287] In another embodiment, the infection is a herpes simplex infection and the subject displays symptoms such as a suppressed immune system (eg, AIDS patients, cancer patients, genetically immunodeficient patients, transplant patients).

[0288] In another embodiment, the infection is a herpes simplex infection and the subject is a neonate or infant.

[0289] In another aspect, the present invention provides a method for inhibiting the recurrence or outbreak of HSV symptoms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the infection is a herpes simplex infection.

[0291] In some embodiments, the infection is an HSV-1 infection.

[0292] In some embodiments, the infection is an HSV-2 infection.

[0293] In some embodiments, the subject is a herpes positive patient.

[0294] In some embodiments, the subject is a herpes simplex positive patient.

[0295] In another aspect, the present invention provides a method for treating or preventing 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, wherein: the infection is resistant to nucleoside antiviral therapy.

[0296] In one embodiment, the infection is a herpes simplex infection.

[0297] In some embodiments, the infection is a herpes simplex infection.

[0298] In another embodiment, the subject is a herpes positive patient.

[0299] In another embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[0300] In another aspect, the invention provides a compound for use as a medicament.

[0301] Combination therapy

[0302] The compounds according to the invention are also suitable for use in combination with other active ingredients for the treatment and prevention of disorders caused by herpes viruses, in particular herpes simplex viruses.

[0303] In one aspect, the present invention provides a method for treating or preventing HSV infection in a subject in need thereof, 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 an antiviral agent.

[0304] In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine.

[0305] In some embodiments, the infection is a herpes simplex infection.

[0306] In some embodiments, the infection is an HSV-1 infection.

[0307] In some embodiments, the infection is an HSV-2 infection.

[0308] In some embodiments, the infection is a herpes simplex infection and the subject displays symptoms such as herpes labialis, genital herpes, HSV-associated keratitis, encephalitis, or pneumonia.

[0309] In another embodiment, the infection is a herpes simplex infection and the subject displays symptoms such as a suppressed immune system (eg, AIDS patients, cancer patients, genetically immunodeficient patients, transplant patients).

[0310] In another embodiment, the infection is a herpes simplex infection and the subject is a neonate or infant.

[0311] In another aspect, the present invention provides a method for inhibiting the recurrence or outbreak of HSV symptoms in a subject in need thereof, 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 an antiviral agent.

[0312] In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine.

[0313] In some embodiments, the infection is a herpes simplex infection.

[0314] In some embodiments, the infection is an HSV-1 infection.

[0315] In some embodiments, the infection is an HSV-2 infection.

[0316] In some embodiments, the subject is a herpes positive patient.

[0317] In some embodiments, the subject is a herpes simplex positive patient.

[0318] In another aspect, the invention provides a compound for use as a medicament.

[0319] In another aspect, the present invention provides a method for treating or preventing 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.

[0320] In some embodiments, the infection is a herpes simplex infection.

[0321] In some embodiments, the infection is an HSV-1 infection.

[0322] In some embodiments, the infection is an HSV-2 infection.

[0323] In some embodiments, the infection is a herpes simplex infection and the subject displays symptoms such as herpes labialis, genital herpes, HSV-associated keratitis, encephalitis, or pneumonia.

[0324] In another embodiment, the infection is a herpes simplex infection and the subject displays symptoms such as a suppressed immune system (eg, AIDS patients, cancer patients, genetically immunodeficient patients, transplant patients).

[0325] In another embodiment, the infection is a herpes simplex infection and the subject is a neonate or infant.

[0326] In another aspect, the present invention provides a method for inhibiting the recurrence or outbreak of HSV symptoms 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.

[0327] In some embodiments, the infection is a herpes simplex infection.

[0328] In some embodiments, the infection is an HSV-1 infection.

[0329] In some embodiments, the infection is an HSV-2 infection.

[0330] In some embodiments, the subject is a herpes positive patient.

[0331] In some embodiments, the subject is a herpes simplex positive patient.

[0332] In another aspect, the invention provides a compound for use as a medicament.

[0333] Formulation and administration

[0334] The compounds of the invention can be converted into conventional formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable carriers and solvents in a known manner. Here, 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 dosage range indicated herein.

[0335] The formulations are prepared, for example, by extending the active compound with solvents and / or excipients, optionally using emulsifiers and / or dispersants, for example, if the diluent used is water, it is possible to use organic solvents as auxiliary solvents as required.

[0336] Administration is carried out in conventional ways, including orally, parenterally, topically, perlingually or intravenously.

[0337] In the case of parenteral administration, solutions or suspensions of the active compound using suitable liquid carriers and excipients may be employed.

[0338] In general, it has been found to be advantageous to administer an amount of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg, of body weight in the case of intravenous administration to achieve effective results, and in the case of oral administration, the dose is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg, of body weight.

[0339] In some cases, it may be necessary to deviate from the amounts mentioned herein, i.e. depending on the body weight or the type of administration route, the individual's reaction to the medicament, its formulation and the time or interval at which the administration occurs. Thus, in some cases, it may be sufficient to proceed with less than the minimum amount mentioned above, while in other cases, the upper limit mentioned herein must be exceeded. In the case of administration in relatively large amounts, it may be advisable to divide this into several separate administrations throughout the day.

[0340] If desired, it may be useful to combine the compounds according to the invention with other active substances, in particular antiviral active substances.

[0341] 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 bases or acids and organic bases or acids). In the case where the compounds of the present invention contain one or more acidic or basic groups, the present invention may also include its corresponding pharmaceutically or toxicologically acceptable salts, specifically its pharmaceutically available salts. Therefore, the compounds of the present invention containing acidic groups can be used according to the present invention, for example, in the form of alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of these salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines (for example, ethylamine, ethanolamine, triethanolamine or amino acids). The compounds of the present invention containing one or more basic groups (i.e., protonated groups) can be used according to the present invention in the form of 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, naphthalene disulfonic 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, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the molecule of the compound of the present invention contains both acidic and basic groups, then in addition to the salt forms mentioned herein, the present invention may also include inner salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The invention also includes all salts of the compounds according to the invention which, owing to low physiological compatibility, are not directly suitable for use in medicine, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0342] Depending on the substitution pattern, the compounds according to the invention may exist in stereoisomeric forms, which are expressed as image and mirror image (enantiomers), or which are not expressed as image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers and the corresponding mixtures thereof. Like diastereomers, racemic forms can be separated in a known manner into stereoisomerically homogeneous components.

[0343] The scope of the present invention includes those compounds which, once inside the body, are merely converted into the actual active compounds of the formula I (so-called prodrugs).

[0344] In actual use, the compounds used in the present invention can be combined in a close mixture with a pharmaceutical carrier as an active ingredient according to conventional pharmaceutical compounding techniques. The carrier can take a wide range of forms, depending on the form of the preparation required for administration, for example, oral or parenteral (including intravenous). When preparing a composition for an oral dosage form, any one of the commonly used pharmaceutical media can be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like, in the case of oral liquid preparations, for example, suspensions, elixirs and solutions; or carriers, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like, in the case of oral solid preparations, for example, powders, hard and soft capsules and tablets, and the solid oral preparations are superior to the liquid preparations.

[0345] Tablets and capsules represent the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are obviously employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques. These compositions and preparations should contain at least 0.1 percent of the active compound. Of course, the percentage of active compound in these compositions may vary and may conveniently be between about 2 percent and about 60 percent of the unit weight. The amount of active compound in these therapeutically useful compositions is such that an effective dose will be obtained. The active compound may also be administered nasally, for example, as a drop or spray or as an eye drop.

[0346] Tablets, pills, capsules, and the like may also contain a binder such as hydroxypropylmethylcellulose or polyvinylpyrrolidone; a diluent or filler such as microcrystalline cellulose, dicalcium phosphate, lactose or mannitol; a disintegrant such as cross-linked carboxymethylcellulose sodium, polyvinylpyrrolidone or sodium starch glycolate; a lubricant such as magnesium stearate fumarate or sodium stearate; a glidant such as silicon dioxide; and a sweetener such as sucrose or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned types of materials.

[0347] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavorings, such as cherry or orange flavor.

[0348] The compounds used in the present invention can also be administered parenterally. Solutions or suspensions of these active compounds can be appropriately mixed with surfactants (e.g., hydroxypropylcellulose, sodium lauryl sulfate, or polysorbate) and prepared in water. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0349] The pharmaceutical form suitable for injectable use includes sterile aqueous solutions or dispersions and sterile powders for preparing sterile injectable solutions or dispersions in real time. In all cases, the form must be sterile and must flow to a certain extent for injection. It must be stable under the conditions of manufacture and storage and must prevent the contamination of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium, containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

[0350] Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to a mammal (especially a human being). For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, and the like can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The compound of the present invention can be administered orally or as eye drops. The compound of the present invention can also be administered orally. The effective dose of the active ingredient used can vary according to the severity of the specific compound used, the mode of administration, the illness being treated, and the illness being treated. This dosage can be easily determined by a technician in the field.

[0351] The compounds of the present invention may also be combined with additional active ingredients, specifically, with one or more active ingredients showing favorable effects in treating any of the disorders or diseases described herein. The compounds of the present invention may be present in the composition (i.e., combination therapy) in combination with at least one effective treatment for a disease or disorder associated with a viral infection, preferably with another active substance (antiviral active compound) associated with a viral infection caused by a herpes virus, such as, specifically, a herpes simplex virus. The at least one effective treatment for a disease or disorder associated with a viral infection (antiviral active compound) is preferably selected from a group consisting of nucleoside drugs, such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, and compounds, such as foscarnet and cidofovir.

[0352] Therefore, the present invention further relates to a pharmaceutical composition comprising one or more of the compounds as described herein and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one other active substance (antivirally active compound) effective in treating a disease or condition associated with a viral infection.

[0353] The novel active compounds can be converted into conventional formulations in a known manner, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, pharmaceutically suitable carriers and solvents. The therapeutically active compounds should therefore be present in each case in a concentration of about 0.1 to 90% by weight of the total mixture, i.e. in an amount sufficient to achieve the dosage range indicated herein.

[0354] The formulations are prepared, for example, by extending the active compound with solvents and / or excipients, optionally using emulsifiers and / or dispersants, for example, if the diluent used is water, it is possible to use organic solvents as auxiliary solvents as required.

[0355] Administration is effected in a customary manner, preferably orally, parenterally or topically, in particular translingually or intravenously.

[0356] In the case of parenteral administration, solutions or suspensions of the active compound using suitable liquid carrier materials may be employed.

[0357] In general, it has been found to be advantageous to administer an amount of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg, of body weight in the case of intravenous administration to achieve effective results, and in the case of oral administration, the dose is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg, of body weight.

[0358] Nevertheless, if necessary, it may be necessary to deviate from the amounts mentioned herein, i.e. depending on the body weight or the type of administration route, the individual's reaction to the medicament, its formulation and the time or interval at which the administration occurs. Thus, in some cases, it may be sufficient to proceed with less than the minimum amount mentioned above, while in other cases, the upper limit mentioned herein must be exceeded. In the case of administration in relatively large amounts, it may be advisable to divide this into several separate administrations throughout the day.

[0359] Examples

[0360] Based on the teachings contained herein and known synthetic procedures in the art, the compounds described herein can be prepared in several ways. In the description of the synthetic methods described below, it should be understood that unless otherwise indicated, all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and post-processing 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 the various parts of the molecule should be compatible with the suggested reagents and reactions. Substituents that are not compatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods are indicated. The starting materials used for the examples can be purchased or easily prepared from known materials by standard methods.

[0361] It is contemplated that at least some of the compounds identified herein as "intermediates" are compounds of the invention.

[0362] abbreviation:

[0363] AcOH Acetic acid

[0364] ACN Acetonitrile

[0365] Boc2O Di-tert-butyl dicarbonate

[0366] nBuLi n-butyllithium

[0367] DCM Dichloromethane

[0368] DIAD Diisopropyl azodicarboxylate

[0369] DIEA Diisopropylethylamine

[0370] DMF N,N-Dimethylformamide

[0371] DMSO Dimethyl sulfoxide

[0372] DPPF 1,1'-Bis(diphenylphosphino)ferrocene

[0373] EtOAc Ethyl acetate

[0374] Et3N Triethylamine

[0375] HATU Azabenzotriazole tetramethyluronium hexafluorophosphate

[0376] h, hr hours

[0377] HPLC High Performance Liquid Chromatography

[0378] LCMS Liquid chromatography-mass spectrometry

[0379] MeOH Methanol

[0380] NMO / NMMO N-Methylmorpholine-N-oxide

[0381] NBS N-bromosuccinimide

[0382] PE Petroleum Ether

[0383] iPrOH Isopropyl alcohol

[0384] rt, rt room temperature

[0385] SFC Supercritical Fluid Chromatography

[0386] TEA Triethylamine

[0387] TBAI Tetrabutylammonium iodide

[0388] TBAB Tetrabutylammonium bromide

[0389] TFA Trifluoroacetic acid

[0390] THF Tetrahydrofuran

[0391] TLC Thin layer chromatography

[0392] XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0393] The following LCMS method has been used to determine the final compounds:

[0394] Method A: X-Bridge BEH C-18 (3x50 mmx2.5 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, at 3.2 min, B concentration is kept at 2% for 4 min.

[0395] Method B: X-select CSH 18 (3x50 mmx2.5 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, at 3.2 min, B concentration was kept at 0% for 4 min.

[0396] Method C: X-select CSH 18 (3x50 mmx2.5 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, at 3.2 min, B concentration was kept at 0% for 4 min.

[0397] Method D: X-select CSH C18 (3x50 mmx2.5μm); mobile phase A: 2mM in ammonium bicarbonate; B: CH3CN; injection volume: 2μL; flow rate: 1.2mL / min, column temperature: 50°C; gradient program: 0% B to 98% B in 2min, hold for 3min, at 3.2min, B concentration was kept at 0% for 4min.

[0398] Method E: X-select CSH 18 (3x50 mmx2.5 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, at 2.6 min, B concentration was kept at 0% for 3 min.

[0399] Example 1. 4-Methyl-2-(2-oxo-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (1)

[0400]

[0401] Step 1. Synthesis of 5-(phenylmethylthio)-4-methylthiazol-2-amine (1-2)

[0402] Benzethiol (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 (eluted with 10 to 20% EtOAc in heptane) to provide 1-2 (25 g, 93.9%) as a dark brown viscous solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 11 H 12 N2S2 calculated value: 236.04; measured value: 236.95[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.35-7.17(m,3H),7.12(dd,J=1.6,7.8Hz,2H),7.06(s,2H),3.77(s,2H),1.73(s,3H)ppm.

[0403] Step 2. Synthesis of 1-(5-(phenylmethylthio)-4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (1-3)

[0404] A mixture of 1-chloro-3-isocyanate propane (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. TBAI (0.15 g, 0.423 mmol) and K2CO3 (1.43 g, 11.016 mmol) were added portionwise to the resulting solution while maintaining the same temperature 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 to 70% EtOAc in heptane) to provide 1-3 (1.3 g, 48.1%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS (ESI): for C 15 H 17 N3OS2 calculated value: 319.08; measured value: 320.10[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.45 (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.

[0405] Step 3. Synthesis of 1-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-2(1H)-one (1-4)

[0406] 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) were added to a stirred solution of 1-3 (0.8 g, 2.50 mmol) in 1,4-dioxane (12 mL). The reaction mixture was purged for 10 min under nitrogen. CuI (0.095 g, 0.50 mmol) was then added under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, which was washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by reverse phase CombiFlash chromatography (eluted with 25% ACN in 0.01M HCOOH in water) to provide 1-4 (0.5 g, 42.3%) as an off-white solid. TLC: 80% EtOAc / heptane (R f:0.5). MS (ESI): for C 26 H 24 N4OS2 calculated value: 472.14; measured value: 473.2[M+1] + .

[0407] Step 4. Synthesis of 2-(4-bromophenyl)pyridine (1-7)

[0408] To a stirred solution of 2-bromopyridine 1-6 (3 g, 18.987 mmol) in toluene: H2O: EtOH (1: 1: 0.2, 150 mL) was added (4-bromophenyl) boronic acid 1-5 (4.9 g, 24.683 mmol) and Na2CO3 (14.90 g, 140.50 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd(PPh3)4 (0.66 g, 0.576 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. 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 20 to 30% EtOAc in heptane) to provide 1-7 as an off-white solid (2 g, 45%). TLC: 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 11 H8BrN calculated value: 232.98; found value: 235.98 [M+2] + . 1 H NMR (400MHz, CDCl3): δ8.69(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.

[0409] Step 5. Synthesis of 4-methyl-2-(2-oxo-3-(4-(pyridin-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (1)

[0410] NCS (0.31 g, 2.38 mmol) was added to a stirred solution of 1-4 (0.3 g, 0.635 mmol) in AcOH / H2O (2.8 / 0.15 mL), and the reaction mixture was stirred for 15 min at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in THF (5 mL) and ammonia (3 mL) was added while stirring was continued for another 4 h at room temperature. 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 layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by reverse phase CombiFlash chromatography (eluted with 10% ACN in 0.01 M HCOOH in water) to provide 1 (26 mg, 9.5%) as an off-white solid. TLC: 100% EtOAc (R f :0.5).

[0411] Example 2. 2-(3-(5'-ethynyl-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (17)

[0412]

[0413] Step 1. Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (2-2)

[0414] A mixture of 2-1 (10 g, 87.71 mmol) and 1-chloro-3-isocyanate propane (15.5 g, 131.57 mmol) in THF (150 mL) was heated at 70 ° C for 6 h. TBAB (1.4 g, 4.38 mmol) and K2CO3 (15.73 g, 114.02 mmol) were added portionwise to the resulting solution, the same temperature was maintained and stirring was continued at 70 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 60 to 70% EtOAc in heptane) to provide 2-2 (10 g, 57.6%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5). MS (ESI): for C8H 11 N3OS calculated value: 197.06; measured value: 198.17[M+1] + . 1H NMR (400MHz, DMSO-d6): δ7.30(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.

[0415] Step 2. Synthesis of 1-(4-bromophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (2-3)

[0416] 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) were added to a stirred solution of 2-2 (5 g, 25.25 mmol) in 1,4-dioxane (200 mL), and the reaction mixture was purged for 10 min under nitrogen, and CuI (0.95 g, 5.05 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (with 50 to 70% EtOAc in heptane) to provide 2-3 (2.5 g, 28.4%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5). MS (ESI): for C 14 H 14 BrN3OS calculated value: 351.00; found value: 354.09 [M+2] + .

[0417] Step 3. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (2-4)

[0418] To a stirred solution of 2-3 (2 g, 5.68 mmol) in anhydrous DCM (20 mL) was added chlorosulfonic acid (1.3 g, 11.363 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid was collected by filtration and dried in vacuo to provide 2-4 (2 g, 81.9%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5), which was used in the next step without further purification. MS (ESI): for C14 H 14 BrN3O4S2 calculated value: 430.96; found value: 434.00 [M+2] + .

[0419] Step 4. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (2-5)

[0420] A mixture of 2-4 (1 g, 2.315 mmol) and POCl3 (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 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 2-5 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 14 H 15 BrN4O3S2 calculated value: 429.98; found value: 431.1 [M+1] + .

[0421] 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)

[0422] To a stirred solution of 2-5 (0.6 g, 1.392 mmol) in 1,4-dioxane (20 mL) was added bis(pinacol)diborane (0.53 g, 2.088 mmol) and KOAc (0.27 g, 2.784 mmol) and the reaction mixture was purged under nitrogen for 10 min. PdCl2(dppf) (0.1 g, 0.14 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 120 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 2-6 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (Rf :0.5). MS (ESI): for C 20 H 27 BN4O5S2 calculated value: 478.15; found value: 479.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.70 (d, J=7.8Hz, 2H), 7.55 (s, 2H), 7.42-7.38 (m, 2H), 4.1 7-4.09(m,2H),3.82-3.74(m,2H),2.44(s,3H),2.26-2.15(m,2H),1.30(s,9H)ppm.

[0423] 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)

[0424] 4-bromo-1-fluoro-2-iodobenzene (0.25 g, 0.836 mmol) and Na2CO3 (0.17 g, 1.673 mmol) were added to a stirred solution of 2-6 (0.4 g, 0.836 mmol) in 1,4-dioxane and water (16:4 mL) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 (eluted with 30 to 40% EtOAc in heptane) to provide 2-7 (0.2 g, 45.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 20 H 18 BrFN4 O3S2 calculated value: 524.00; found value: 525.00 [M+1] + .

[0425] 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)

[0426] 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 min. Pd (PPh3) 2Cl2 (27 mg, 0.038 mmol) and ethynyltrimethylsilane (56 mg, 0.571 mmol) were added under a nitrogen atmosphere and then the reaction mixture was heated at 120 ° C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 provide 17 (5 mg, 5.61%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0427] 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)

[0428]

[0429] Step 1. Synthesis of 4-(2-bromo-4-fluorophenyl)-2-methylbut-3-yn-2-ol (3-2)

[0430] To a stirred solution of compound 3-1 (1 g, 3.323 mmol) in DIPEA (10 mL) was added 2-methylbutan-3-yn-2-ol (0.49 g, 4.984 mmol) and the reaction mixture was purged under nitrogen for 10 min. CuI (63 mg, 0.332 mmol) and Pd (dppf) Cl2 (0.11 g, 0.166 mmol) were added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (eluted with 5 to 10% EtOAc in heptane) to provide 3-2 (0.8 g, 94.1%) as a brown oil. TLC: 10% EtOAc / heptane (R f :0.5).

[0431] 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)

[0432] 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 min. To this resulting reaction mixture was added Pd(dppf)Cl2 (30 mg, 0.0418 mmol) under a nitrogen atmosphere and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 preparative HPLC to provide 19 (10 mg, 4.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0433] 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)

[0434]

[0435] Step 1. Synthesis of 2-(3-bromophenyl)thiazole (4-2)

[0436] 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 K3PO4 (3.18 g, 15.242 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture was added Pd(dppf)Cl2 (0.445 g, 0.6097 mmol) under a nitrogen atmosphere and the reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 chromatography (eluted with 2 to 3% EtOAc in heptane) to provide 4-2 (0.2 g, 13.7%) as an off-white solid. TLC: 10% EtOAc / heptane (R f :0.5).

[0437] 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)

[0438] 2-(3-bromophenyl)thiazole (0.1 g, 0.418 mmol) was added to a stirred solution of 8 (0.2 g, 0.418 mmol) in 1,4-dioxane: water (4:1, 10 mL), followed by K3PO4 (0.221 g, 1.04 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. Pd(dppf)Cl2 (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 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 preparative HPLC to provide 30 (14 mg, 6.5%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.5).

[0439] Example 5. 4-Methyl-2-(2-oxo-3-(4-(thiazol-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (42)

[0440]

[0441] Step 1. Synthesis of 4-methyl-2-(2-oxo-3-(4-(thiazol-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)thiazole-5-sulfonamide (42)

[0442] 2-bromothiazole (0.1 g, 0.626 mmol) and K3PO4 (0.13 g, 0.626 mmol) were added to a stirred solution of 2-6 (0.15 g, 0.313 mmol) in 1,4-dioxane and water (8:2 mL) and the reaction mixture was purged under nitrogen for 10 min. Pd (dppf) Cl2 (23 mg, 0.0313 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 provide 42 (20 mg, 15.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0443] Example 6. 2-(3-(4-(Benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (51)

[0444]

[0445] Step 1. Synthesis of ethyl 4-(3-(4-methylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoate (6-1)

[0446] To a stirred solution of 2-2 (3.1 g, 15.656 mmol) in 1,4-dioxane (100 mL) was added 4-iodobenzoic acid ethyl ester (4.3 g, 15.656 mmol), K2CO3 (4.3 g, 3.131 mmol) and 1,2-dimethylethylenediamine (0.7 g, 1.269 mmol) and the reaction mixture was purged under nitrogen for 10 min. CuI (0.6 g, 3.131 mmol) was then added to the resulting reaction mixture under a nitrogen atmosphere and the resulting reaction mixture was heated at 100 ° C for 24 h. After the reaction was completed, the reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 50 to 70% EtOAc in heptane) to provide 6-1 (3 g, 57.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 17 H 19 N3O3S calculated value: 345.1; measured value: 346.1[M+1] + .

[0447] Step 2. Synthesis of 2-(3-(4-(ethoxycarbonyl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (6-2)

[0448] Chlorosulfonic acid (2 g, 17.39 mmol) was added to a stirred solution of 6-1 (3 g, 8.695 mmol) in anhydrous DCM (50 mL) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 6-2 (3 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5), which was used in the next step without further purification. MS (ESI): for C 17 H 19 N3O6S2 calculated value: 425.1; found value: 426.1[M+1] + .

[0449] Step 3. Synthesis of ethyl 4-(3-(4-methyl-5-sulfamoylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoate (6-3)

[0450] A mixture of 6-2 (0.5 g, 1.176 mmol) and POCl (5 mL) was allowed to stir 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 ammonia (8 mL) was added at 0 ° C while stirring was continued for another 4 h at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 6-3 (0.3 g, thick) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5), which was used in the next step without further purification. MS (ESI): for C 17 H 20 N4O5S2 calculated value: 424.09; found value: 424.92 [M+1] + .

[0451] Step 4. Synthesis of 4-(3-(4-methyl-5-sulfamoylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzoic acid (6-4)

[0452] To a stirred solution of 6-3 (0.2 g, 0.471 mmol) in THF: MeOH: H2O (8: 1: 1 mL) at 0 ° C was added lithium hydroxide monohydrate (39 mg, 0.943 mmol) portionwise. The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 3 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was treated with saturated KHSO4 solution and the precipitated solid obtained was collected by filtration and dried in vacuo to provide 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): for C 15 H 16 N4O5S2 calculated value: 396.06; found value: 397.2 [M+1] + .

[0453] Step 5. Synthesis of 2-(3-(4-(1,3,4-oxadiazol-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (51)

[0454] To a stirred solution of 6-4 (0.2 g, 0.505 mmol) in DCM / EtOH (10 / 10 mL) was added (N-isocyanoimido)triphenylphosphine (0.30 g, 1.010 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 16 h. After the reaction was complete (monitored by TLC), the resulting reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to provide 51 (36 mg, 16.9%) as an off-white solid.

[0455] Example 7. 2-(3-(4-(Benzo[d]thiazol-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (67)

[0456]

[0457] Step 1. Synthesis of 2-(3-(4-(Benzo[d]thiazol-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (67)

[0458] 7-bromobenzo[d]thiazole (0.18 g, 0.836 mmol) was added to a stirred solution of 2-6 (0.2 g, 0.418 mmol) in 1,4-dioxane and water (5 / 0.5 mL), followed by K2CO3 (0.17 g, 0.836 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd(dppf)Cl2 (30 mg, 0.041 mmol) was added to the resulting solution under a nitrogen atmosphere and the reaction mixture was heated at 120 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc, 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 provide 67 (10 mg, 5%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5).

[0459] Example 8. 2-(3-(4-(Benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (71)

[0460]

[0461] Step 1. Synthesis of 2-(3-(4-(Benzo[d]thiazol-4-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (71)

[0462] To a stirred solution of 2-6 (0.2 g, 0.418 mmol) in 1,4-dioxane and water (4: 1, 10 mL) was added 4-bromobenzo [d] thiazole (0.13 g, 0.627 mmol) and Na2CO3 (88 mg, 0.836 mmol) and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution was added Pd (dppf) Cl2 (30 mg, 0.0406 mmol) under a nitrogen atmosphere and the reaction mixture was heated at 100 ° C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 provide 71 (30 mg, 15%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0463] Example 9. 2-(3-(2,5-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (99)

[0464]

[0465] Step 1. Synthesis of 1-(4-bromo-2,5-difluorophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (9-1)

[0466] To a stirred solution of 2-2 (1.5 g, 7.614 mmol) in 1,4-dioxane (30 mL) was added 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), and the reaction mixture was purged under nitrogen for 10 min. To this resulting reaction mixture was added CuI (0.3 g, 1.522 mmol) under nitrogen atmosphere. The reaction mixture was heated at 120°C for 24 h. The reaction mixture was filtered. 545 beds and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, then washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude compound was purified by CombiFlash chromatography (eluted with 50 to 70% EtOAc in heptane) to provide 9-1 (0.8 g, 27.1%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 14 H 12 BrF2N3OS calculated: 386.99; found: 390.0 [M+2] + . 1 HNMR (400MHz, DMSO-d6): δ7.86 (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.

[0467] Step 2. Synthesis of 2-(3-(4-bromo-2,5-difluorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (9-2)

[0468] To a stirred solution of 9-1 (0.89 g, 2.294 mmol) in anhydrous DCM (20 mL) was added chlorosulfonic acid (0.38 g, 5.734 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 9-2 (0.75 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5), which was used in the next step without further purification. MS (ESI): for C 14 H 12 BrF2N3O4S2 calculated value: 466.94; found value: 469.85 [M+2] + . 1H NMR (400MHz, DMSO-d6): δ7.87(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.

[0469] Step 3. Synthesis of 2-(3-(4-bromo-2,5-difluorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (9-3)

[0470] A mixture of 9-2 (1 g, 2.136 mmol) and POCl (10 mL) was allowed to stir 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 ammonia (5 mL) was added at 0 ° C while stirring was continued for another 2 h at room temperature. 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 to 40% EtOAc in heptane) to provide 9-3 (0.8 g, 80.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 14 H 13 BrF2N4O3S2 calculated value: 465.96; found value: 467.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.93-7.85(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.

[0471] Step 4. Synthesis of 2-(3-(2,5-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (99)

[0472] Phenylboronic acid (78 mg, 0.642 mmol) and Na2CO3 (90 mg, 0.856 mmol) were added to a stirred solution of 9-3 (0.2 g, 0.428 mmol) in 1,4-dioxane and water (4:1 mL) and the reaction mixture was purged under nitrogen for 10 min. Pd(dppf)Cl2 (31 mg, 0.043 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 110 °C for 12 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (with 80 to 90% EtOAc in heptane) to provide 99 (0.12 g, 60.6%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0473] Example 10. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,3-diazepan-1-yl)-4-methylthiazole-5-sulfonamide (101)

[0474]

[0475] Step 1. Synthesis of 4-((4-methylthiazol-2-yl)amino)butan-1-ol (10-2)

[0476] 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 the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. 545 pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 20 to 30% EtOAc in heptane] to provide 10-2 (4 g, 28.7%) as a light brown oil. TLC: 20% EtOAc / heptane (R f :0.2). MS (ESI): for C8H 14 N2OS calculated value: 186.27; measured value: 187.0[M+1] + . 1H NMR (400MHz, DMSO-d6): δ7.37(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.

[0477] Step 2. Synthesis of 3-(4-bromophenyl)-1-(4-hydroxybutyl)-1-(4-methylthiazol-2-yl)urea (10-3)

[0478] Compound 1-bromo-4-isocyanatobenzene (1.6 g, 8.064 mmol) was added to a stirred solution of 10-2 (1.5 g, 8.064 mmol) in 1,4-dioxane (30 mL). The resulting reaction mixture was allowed to stir for 12 h at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc, 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 to 40% EtOAc in heptane] to provide 10-3 (1.1 g, 38.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.2). MS (ESI): for C 15 H 18 BrN3O2S calculated value: 383.03; found value: 386 [M+2] + .

[0479] Step 3. Synthesis of 4-methylbenzenesulfonic acid 4-(3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)ureido)butyl ester (10-4)

[0480] 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) at 0 ° C, followed by p-toluenesulfonyl chloride (0.6 g, 3.125 mmol). The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. 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 to 40% EtOAc in heptane] to provide 10-4 (1 g, 71.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 22H 24 BrN3O4S2 calculated value: 537.04; found value: 538.14 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.05 (s, 1H), 7.75 (d, J = 8.3Hz, 2H), 7.55-7.46 (m, 4H), 7.46-7.4 1(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.

[0481] Step 4. Synthesis of 1-(4-bromophenyl)-3-(4-methylthiazol-2-yl)-1,3-diazepan-2-one (10-5)

[0482] To a stirred solution of 10-4 (1 g, 1.858 mmol) in anhydrous DMF (10 mL) at 0 ° C. under nitrogen atmosphere was added NaH (60% w / w in mineral oil, 0.134 g, 2.788 mmol) in small portions and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 15 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 10-5 (0.6 g, 88.2%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5), which was used in the next step without further purification. MS (ESI): for C 15 H 16 BrN3OS calculated value: 365.02; found value: 368 [M+2] + . 1 H NMR (400MHz, DMSO-d6): δ7.55(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.

[0483] 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)

[0484] To a stirred solution of 10-5 (0.6 g, 1.639 mmol) in 1,4-dioxane:HO (4:1, 20 mL) was added (2,5-difluorophenyl)boric acid (0.38 g, 2.46 mmol) and CsCO (1 g, 3.278 mmol) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layer was 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 provide 10-6 (0.6 g, 92.3%) as a yellow solid. TLC: 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 21 H 19 F2N3OS calculated value: 399.12; measured value: 400.05[M+1] + . 1 HNMR (400MHz, DMSO-d6): δ7.60(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.

[0485] 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)

[0486] Chlorosulfonic acid (0.15 mL, 2.255 mmol) was added to a stirred solution of 10-6 (0.3 g, 0.751 mmol) in anhydrous DCM (10 mL) at -5 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 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): for C 21 H 19 F2N3O4S2 calculated value: 479.08; found value: 480.21[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.60(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.

[0487] 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)

[0488] Oxalyl chloride (0.1 mL, 1.252 mmol) was added to a stirred solution of 2-7 (0.2 g, 0.417 mmol) in DCM (10 mL) at -10 ° C in an inert atmosphere, followed by DMF (catalyst). The resulting reaction mixture was slowly warmed to room temperature and allowed to stir 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 ammonia (5 mL) was added at 0 ° C while continuing to stir for another 1 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane), followed by preparative HPLC to provide 101 (40 mg, 20%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0489] Example 11. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-sulfonamide (104)

[0490]

[0491] Step 1. Synthesis of 4'-bromo-2,5-difluoro-1,1'-biphenyl (11-7)

[0492] To a stirred solution of 11-6 (5 g, 17.674 mmol) in 1,4-dioxane / H2O (50 mL / 5 mL) was added (2,5-difluorophenyl)boronic acid (11-5) (3.07 g, 19.441 mmol) and K3PO4 (7.5 g, 35.348 mmol) and the reaction mixture was purged under nitrogen for 10 min. PdCl2(dppf) (1.29 g, 1.767 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 1 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. 545 pad and washed with ethyl acetate. The filtrate 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 100% heptane) to provide 11-7 (2.3 g, 48.6%) as an off-white solid. TLC: 100% heptane (R f :0.5). 1 H NMR (400MHz, CDCl3) δ7.58 (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.

[0493] Step 2. Synthesis of 1-(4-methylthiazol-2-yl)imidazolidin-2-one (11-2)

[0494] 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. To this resulting solution, TBAB (0.7 g, 2.192 mmol) and K2CO3 (12.10 g, 87.718 mmol) were added portionwise, the same temperature was maintained 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 to 70% EtOAc in heptane) to provide 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): δ7.52 (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.

[0495] Step 3. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)imidazolidin-2-one (11-3)

[0496] To a stirred solution of 11-2 (2 g, 10.752 mmol) in 1,4-dioxane (50 mL) was added 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). The reaction mixture was purged for 10 min under nitrogen. CuI (0.4 g, 2.150 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 50 to 70% EtOAc in heptane) to provide 11-3 (0.35 g, 17.5%) as an off-white solid. TLC: 60% EtOAc / heptane (R f :0.5). MS (ESI): for C 19 H 15F2N3OS calculated value: 371.09; measured value: 372.35[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.77(d,J=8.3Hz,2H),7.69-7.57(m,2H),7.49-7.3 0(m,2H),7.30-7.19(m,1H),6.79(s,1H),4.21-4.05(m,4H),2.28(s,3H)ppm.

[0497] 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)

[0498] To a stirred solution of 11-3 (0.3 g, 0.808 mmol) in anhydrous DCM (5 mL) was added chlorosulfonic acid (0.16 mL, 2.425 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 11-4 (0.2 g, 66.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5), which was used in the next step without further purification.

[0499] Step 5. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-sulfonamide (104)

[0500] Oxalyl chloride (0.1 mL, 1.327 mmol) was added to a stirred solution of 11-4 (0.2 g, 0.442 mmol) in DCM (5 mL) at 0 ° C in an inert atmosphere, followed by the addition of DMF (catalyst). The resulting reaction mixture was slowly warmed to room temperature and allowed to stir 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 ammonia (5 mL) was added at 0 ° C while continuing to stir for another 1 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 0 to 1% MeOH in DCM) followed by preparative HPLC to provide 104 (8 mg, 4.2%) as an off-white solid.

[0501] Example 12. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (107)

[0502]

[0503] Step 1. Synthesis of 3-((4-methylthiazol-2-yl)amino)butan-1-ol (12-1)

[0504] 3-aminobutan-1-ol (1.0 g, 11.278 mmol) was added to a stirred solution of 10-1 (1 g, 7.518 mmol) in DMSO (10 mL), followed by K2CO3 (2.5 g, 18.795 mmol) and the reaction mixture was purged under nitrogen for 10 min. CuI (0.142 g, 0.751 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere and the reaction mixture was heated at 120 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluted with 30 to 70% EtOAc in heptane) to provide 12-1 (0.35 g, 25%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0505] Step 2. Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-4-methylthiazol-2-amine (12-2)

[0506] To a stirred solution of 12-1 (1.5 g, 8.064 mmol) in anhydrous DCM (20 mL) at 0 ° C under a nitrogen atmosphere, imidazole (1.09 g, 16.128 mmol) was added in small portions and the resulting reaction mixture was stirred for 10 to 15 min at the same temperature. Tert-butyldimethylsilyl chloride (1.38 g, 8.870 mmol) was added to this reaction mixture at 0 ° C and then the reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 12-2 (1 g, 41.6%) as a yellow oil. TLC: 30% EtOAc / heptane (R f :0.5).

[0507] Step 3. Synthesis of 3-(4-bromophenyl)-1-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-1-(4-methylthiazol-2-yl)urea (12-3)

[0508] To a stirred solution of 12-2 (1 g, 3.333 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-4-isocyanatobenzene (0.78 g, 4.00 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluted with 30 to 40% EtOAc in heptane] to provide 12-3 (1 g, 62.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0509] Step 4. Synthesis of 3-(4-bromophenyl)-1-(4-hydroxybutan-2-yl)-1-(4-methylthiazol-2-yl)urea (12-4)

[0510] Tetrabutylammonium fluoride (1M solution in THF, 4.02mL, 4.024mmol) was added dropwise to a stirred solution of 12-3 (1 g, 2.012mmol) in anhydrous THF (5mL) at 0°C under a nitrogen atmosphere. The resulting reaction mixture was slowly warmed to room temperature and stirred for 4h. After the reaction was completed (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 (eluted with 20 to 30% EtOAc in heptane) to provide 12-4 (0.5g, thick) as a light yellow oil. TLC: 50% EtOAc / heptane (R f :0.5).

[0511] Step 5. Synthesis of 1-(4-bromophenyl)-4-methyl-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (12-5)

[0512] Triphenylphosphine (0.68 g, 2.610 mmol) was added to a stirred solution of 12-4 (0.5 g, 1.305 mmol) in toluene (5 mL) at 0 ° C, 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 the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 20 to 30% EtOAc in heptane) to provide 12-5 (0.3 g, 62.8 g) as a light yellow oil. TLC: 50% EtOAc / heptane (R f :0.5).

[0513] Step 6. Synthesis of 2-(3-(4-bromophenyl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (12-6)

[0514] Chlorosulfonic acid (0.19 g, 1.643 mmol) was added to a stirred solution of 12-5 (0.3 g, 0.821 mmol) in anhydrous DCM (5 mL) at 0 ° C in an inert atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The obtained crude residue was purified by trituration with ether. The obtained solid was filtered off and dried in vacuo to provide 12-6 (0.25 g, crude) as an off-white solid, TLC: 40% EtOAc / heptane (R f :0.3), which was used in the next step without further purification.

[0515] Step 7. Synthesis of 2-(3-(4-bromophenyl)-6-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (12-7)

[0516] The mixture of 12-6 (0.25 g, 0.327 mmol) and POCl (3 mL) was allowed to stir 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 ammonia (5 mL) was added at 0 ° C and continued to stir for another 16 h at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 40 to 50% EtOAc in heptane) to provide 12-7 (0.15 g, 78%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0517] 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)

[0518] To a stirred solution of 12-7 (0.15 g, 0.337 mmol) in 1,4-dioxane:H2O (4:1, 10 mL) was added (2,5-difluorophenyl)boronic acid (0.8 g, 0.506 mmol) and K3PO4 (0.143 g, 0.674 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd(dppf)Cl2 (24.7 mg, 0.0337 mmol) was added under nitrogen atmosphere and the reaction mixture was heated at 100 °C for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. 545 pad 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 afford 107 (90 mg, 55.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0519] 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)

[0520]

[0521] Step 1. Synthesis of 1-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-3-(4-bromophenyl)urea (13-1)

[0522] To a stirred solution of 1-2 (2.5 g, 10.593 mmol) in 1,4-dioxane (25 mL) was added 1-bromo-4-isocyanatobenzene (2.08 g, 10.593 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 13-1 (2 g, 44.7%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5), which was used in the next step without further purification. 1HNMR (400MHz, DMSO-d6): δ10.56(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.

[0523] Step 2. Synthesis of 5-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-7-(4-bromophenyl)-5,7-diazaspiro[2.5]octan-6-one (13-2)

[0524] To a stirred solution of 13-1 (1.5 g, 3.464 mmol) in anhydrous DMF (30 mL) was added Cs2CO3 (3.37 g, 10.392 mmol) in a small portion at 0 ° C under a nitrogen atmosphere 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 this reaction mixture at 0 ° C and then the reaction mixture was slowly warmed to room temperature and stirred at 100 ° C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 13-2 (0.4 g, 23.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 23 H 22 Calculated for BrN3OS2: 499.04; found: 500.1 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ7.58(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.

[0525] Step 3. Synthesis of 2-(7-(4-bromophenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (13-3)

[0526] NCS (0.1 g, 0.751 mmol) was added to a stirred solution of 13-2 (0.1 g, 0.200 mmol) in AcOH / H2O (2 mL / 0.2 mL), and the reaction mixture was stirred for 30 min at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was dissolved in THF (1 mL) and ammonia (2 mL) was added at 0 ° C. and stirring was continued for another 16 h at the same temperature. The reaction mixture was concentrated to dryness under reduced pressure. The obtained reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluted with 1 to 2% MeOH in DCM) to provide 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): δ7.62-7.54(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.

[0527] 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)

[0528] To a stirred solution of 13-3 (90 mg, 0.197 mmol) in 1,4-dioxane and water (2:0.4 mL) was added (2,5-difluorophenyl) boronic acid (46.74 mg, 0.296 mmol) and K3PO4 (0.10 g, 0.492 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd(dppf)Cl2 (14 mg, 0.0197 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 preparative HPLC to provide 110 (10 mg, 10.3%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3).

[0529] 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)

[0530]

[0531] Step 1. Synthesis of (1-(((4-methylthiazol-2-yl)amino)methyl)cyclopropyl)methanol (14-1)

[0532] To a stirred solution of 10-1 (3 g, 22.455 mmol) in DMSO (50 mL) was added compound 2 (3.4 g, 33.682 mmol mmol), followed by K2CO3 (4.65 g, 33.682 mmol) and the reaction mixture was purged under nitrogen for 10 min. CuI (0.43 g, 2.245 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere and the reaction mixture was heated at 120 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluted with 10 to 20 to 70% EtOAc in heptane) to provide 14-1 (0.8 g, 18%) as an off-white solid. TLC: 20% EtOAc / heptane (R f :0.5). MS (ESI): for C9H 14 N2OS calculated value: 198.08; measured value: 199.1[M+1] + .

[0533] Step 2. Synthesis of N-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4-methylthiazol-2-amine (14-2)

[0534] To a stirred solution of 14-1 (0.4 g, 2.020 mmol) in anhydrous DCM (20 mL) at 0 ° C under a nitrogen atmosphere, imidazole (0.20 g, 3.030 mmol) was added in small portions and the resulting reaction mixture was stirred for 10 to 15 min at the same temperature. Tert-butyldimethylsilyl chloride (0.36 g, 2.424 mmol) was added to this reaction mixture at 0 ° C and the reaction mixture was then slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 14-2 (0.7 g, 55.5%) as a yellow oil. TLC: 20% EtOAc / heptane (R f :0.5).

[0535] Step 3. Synthesis of 3-(4-bromophenyl)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1-(4-methylthiazol-2-yl)urea (14-3)

[0536] 1-Bromo-4-isocyanatobenzene (0.22 g, 1.121 mmol) was added to a stirred solution of 14-2 (0.35 g, 1.121 mmol) in 1,4-dioxane (10 mL) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluted with 30 to 40% EtOAc in heptane] to provide 14-3 (0.5 g, 43.8%) as an off-white solid. TLC: 20 to 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 22 H 32 BrN3O2SSi calculated value: 509.12; found value: 512.13 [M+2] + .

[0537] Step 4. Synthesis of 3-(4-bromophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1-(4-methylthiazol-2-yl)urea (14-4)

[0538] Tetrabutylammonium fluoride (1M solution in THF, 1 mL, 0.980 mmol) was added dropwise to a stirred solution of 14-3 (0.25 g, 0.490 mmol) in anhydrous THF (5 mL) at 0 ° C under a nitrogen atmosphere. The resulting reaction mixture was slowly warmed to room temperature and stirred for 4 h. After the reaction was completed (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 (eluted with 20 to 30% EtOAc in heptane) to provide 14-4 (0.4 g, thick) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 22 H 32 BrN3O2SSi calculated value: 395.03; found value: 396.1[M+1] + .

[0539] Step 5. Synthesis of 5-(4-bromophenyl)-7-(4-methylthiazol-2-yl)-5,7-diazaspiro[2.5]octan-6-one (14-5)

[0540] Triphenylphosphine (0.2 g, 0.759 mmol) was added to a stirred solution of 14-4 (0.2 g, 0.506 mmol) in toluene (5 mL) at 0 ° C, 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 the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 20 to 30% EtOAc in heptane) to provide 14-5 (0.24 g, 63.1%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5). MS (ESI): for C 16 H 16 BrN3OS calculated value: 377.02; found value: 377.90 [M+1] + .

[0541] 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)

[0542] To a stirred solution of 14-5 (0.12 g, 0.317 mmol) in anhydrous DCM (10 mL) was added chlorosulfonic acid (0.11 g, 0.952 mmol) at 0 ° C in an inert atmosphere, 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 obtained crude residue was purified by trituration with ether. The obtained solid was filtered off and dried in vacuo to provide 14-6 (0.15 g, crude) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3), which was used in the next step without further purification. MS (ESI): for C 16 H 16 BrN3O4S2 calculated value: 456.98; found value: 459.7 [M+2] + .

[0543] Step 7. Synthesis of 2-(7-(4-bromophenyl)-6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4-methylthiazole-5-sulfonamide (14-7)

[0544] A mixture of 14-6 (0.15 g, 0.327 mmol) and POCl3 (1.5 mL) was allowed to stir 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 ammonia (5 mL) was added at 0 ° C while stirring was continued for another 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by trituration with ether. The solid obtained was filtered off and dried in vacuo to provide 14-7 (0.1 g, crude) as a light brown solid. TLC: 30% EtOAc / heptane (R f :0.3), which was used in the next step without further purification. MS (ESI): for C 16 H 17 BrN4O3S2 calculated value: 455.99; found value: 458.7 [M+2] + .

[0545] 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)

[0546] 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 to a stirred solution of 14-7 (0.1 g, 0.218 mmol) in 1,4-dioxane:HO (4:1, 10 mL) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad 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 provide 113 (20 mg, 20%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3).

[0547] Example 15. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N,4-dimethylthiazole-5-sulfonamide (116)

[0548]

[0549] Step 1. Synthesis of 1-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (15-1)

[0550] 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 to a stirred solution of 1-3 (0.5 g, 1.567 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was purged under nitrogen for 10 min. CuI (60 mg, 0.313 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 50 to 70% EtOAc in heptane) to provide 15-1 as an off-white solid (0.25 g, 31.6%). TLC: 60% EtOAc / heptane (R f :0.5). MS (ESI): for chemical formula C 27 H 23 F2N3OS2 calculated value: 507.13; measured value: 508.44[M+1] + .

[0551] 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)

[0552] To a stirred solution of 15-1 (0.15 g, 0.295 mmol) in AcOH:H2O (1.5:0.1 mL) was added NCS (0.15 g, 1.10 mmol), and the reaction mixture was stirred at room temperature for 30 min. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (2 mL), methylamine (33% by weight solution in methanol, 3 mL) was added to the resulting solution at 0 ° C and continued to stir for another 1 h at room temperature. 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 layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to provide 116 (15 mg, 10.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5).

[0553] Example 16. 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonylimino)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (139)

[0554]

[0555] Step 1. Synthesis of 4-methyl-5-(methylthio)thiazol-2-amine (16-1)

[0556] To a stirred solution of 1-1 (1 g, 5.181 mmol) in methanol (10 mL) was added sodium thiomethoxide (0.544 g, 7.77 mmol) at 0 ° C. 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 layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluted with 10 to 20% EtOAc in heptane) to provide 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) δ7.08(br s,2H),2.21(s,3H),2.12(s,3H).

[0557] Step 2. Synthesis of 1-(4-methyl-5-(methylthio)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (16-2)

[0558] 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. TBAI (69 mg, 0.187 mmol) and K2CO3 (0.77 g, 5.62 mmol) were added portionwise to the resulting solution, the same temperature was maintained 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 to 70% EtOAc in heptane) to provide 16-2 (0.5 g, 54.8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C9H 13 N3OS2 calculated value: 174.03; measured value: 174.77[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.44(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.

[0559] 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)

[0560] 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 to a stirred solution of 16-2 (0.5 g, 2.057 mmol) in 1,4-dioxane (6 mL), and the reaction mixture was purged under nitrogen for 10 min. CuI (78 mg, 0.41 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated at 110 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (eluted with 50 to 70% EtOAc in heptane) to provide 16-3 (0.4 g, 45%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 21 H 19 F2N3OS2 calculated value: 431.09; measured value: 432.1[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.63-7.59(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.

[0561] Step 4. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonylimino)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (139)

[0562] To a stirred solution of 16-3 (0.1 g, 0.23 mmol) in ACN: MeOH (2: 2 mL) was added ammonium formate (0.054 g, 0.69 mmol) and PhI (OAc) 2 (0.34 g, 0.92 mmol). The resulting reaction mixture was allowed to stir for 2 h at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude residue was dissolved in ethyl acetate and washed with water. The combined organic layer was 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) followed by preparative HPLC to provide 139 (15 mg, 14%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.5).

[0563] Example 17. (R)-1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonylimino)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (140) and (S)-1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(S-methylsulfonylimino)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (141).

[0564]

[0565] Chiral separation of compound 139 under the following conditions afforded 140 and 141 as off-white solids.

[0566] Chiral separation conditions for 140

[0567] Chiral HPLC: Rt 14.02min, 100%

[0568] Chiral PAK IC (150x4.6 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.

[0569] Chiral separation conditions for 141

[0570] Chiral HPLC: Rt 16.02min, 99.05%

[0571] Chiral PAK IC (150x4.6 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.

[0572] The stereochemistry of 140 and 141 was arbitrarily assigned, respectively.

[0573] Example 18. 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(5-(isopropylsulfonyl)-4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (162)

[0574]

[0575] Step 1. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (18-1)

[0576] To a stirred solution of 2-2 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL) was 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 min. To this resulting reaction mixture was added 1,2-dimethylethylenediamine (0.9 g, 10.152 mmol) under nitrogen atmosphere. The reaction mixture was heated at 120 °C for 16 h in a sealed tube. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (eluted with 30 to 40% EtOAc in heptane) to provide 18-1 (4.1 g, 41.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 20 H 17 F2N3OS calculated value: 385.11; measured value: 385.90[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.61(d,J=7.8Hz,2H),7.54-7.35(m,4H),7.35-7.21(m,1H),6.7 0(s,1H),4.17(t,J=5.6Hz,2H),3.81(t,J=4.9Hz,2H),2.26(s,3H),2.24-2.21(m,2H)ppm.

[0577] 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)

[0578] 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 the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 18-2 (0.7 g, 58.3%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 20 H 16 BrF2N3OS calculated: 463.02; found: 466.0 [M+2] + .

[0579] 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)

[0580] To a stirred solution of 18-2 (0.5 g, 1.079 mmol) in DMF (10 mL) was added propane-2-sulfinic acid sodium salt (0.56 g, 4.319 mmol) and CS2CO3 (0.87 g, 2.69 mmol) and then subsequently CuI (21 mg, 0.1079 mmol) was added, 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 and extracted with EtOAc, 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 preparative HPLC to provide 162 (8 mg, 1.5%) as an off-white solid.

[0581] Example 19. 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonamide (169)

[0582]

[0583] Step 1. Synthesis of 4-(trifluoromethyl)thiazol-2-amine (19-2)

[0584] To a stirred solution of 19-1 (2.7 g, 14.210 mmol) in ethanol (50 mL) was added thiourea (2.16 g, 28.42 mmol) 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 to 30% EtOAc in heptane) to provide 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] + .

[0585] Step 2. Synthesis of 1-(4-(trifluoromethyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (19-3)

[0586] 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) was added TBAI (0.38 g, 1.190 mmol) and K2CO3 (4.28 g, 30.951 mmol) portionwise, and the resulting reaction mixture was stirred at 70 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 30 to 40% EtOAc in heptane) to provide 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] + .

[0587] Step 3. Synthesis of 1-(4-bromophenyl)-3-(4-(trifluoromethyl)thiazol-2-yl)tetrahydropyrimidin-2(1H)-one (19-4)

[0588] 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 min. To this resulting reaction mixture was added 1,2-dimethylethylenediamine (0.378 g, 4.302 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h in a sealed tube. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (eluted with 30 to 40% EtOAc in heptane) to provide 19-4 (2 g, 45.9%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 14 H 11 BrF3N3OS calculated value: 404.98; found value: 405.80 [M+1] + .

[0589] Step 4. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonic acid (19-5)

[0590] To a stirred solution of 19-4 (0.5 g, 1.234 mmol) in anhydrous DCM (8 mL) was added chlorosulfonic acid (0.4 mL, 4.938 mmol) at 0 ° C in an inert atmosphere 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 obtained crude residue was purified by trituration with ether. The obtained solid was filtered off and dried in vacuo to provide 19-5 (0.5 g, crude) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3). MS (ESI): for C 14 H 11 BrF3N3O4S2 calculated value: 484.93; found value: 485.65 [M+1] + .

[0591] Step 5. Synthesis of 2-(3-(4-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(trifluoromethyl)thiazole-5-sulfonamide (19-6)

[0592] A stirring solution of 19-5 (0.5 g, 1.030 mmol) in POCl3 (6 mL) was allowed to stir 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 for another 16 h at room temperature. 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 to 40% EtOAc in heptane) to provide 19-6 (0.2 g, 40.1%) as an off-white solid. MS (ESI): for C 14 H 12 BrF3N4O3S2 calculated value: 483.95; found value: 484.85 [M+1] + .

[0593] 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)

[0594] To a stirred solution of 19-6 (0.2 g, 0.413 mmol) in 1,4-dioxane:HO (5:1 mL) was added (2,5-difluorophenyl)boric 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 min. Pd(dppf)Cl (30 mg, 0.041 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad 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 10 to 30% EtOAc in heptane) to provide 169 (25 mg, 11.6%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.3).

[0595] Example 20. 2-(3-((2',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (172)

[0596]

[0597] Step 1. Synthesis of 1-(3-bromobenzyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (20-1)

[0598] To a stirred solution of 2-2 (4 g, 20.304 mmol) in anhydrous THF (80 mL) was added NaH (60% w / w in mineral oil, 1.21 g, 30.456 mmol) in a small portion at 0 ° C under a nitrogen atmosphere and the resulting reaction mixture was stirred for 30 min at the same temperature. 1-Bromo-4-(bromomethyl)benzene (6 g, 24.36 mmol) was added to this reaction mixture at 0 ° C and the resulting reaction mixture was stirred for 2 h at the same temperature. After the reaction was completed (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 (using a gradient method of 50 to 60% EtOAc in heptane) to provide 20-1 (5.21 g, 70.3%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 15 H 16 BrN3OS calculated value: 365.02; found value: 368 [M+2] + . 1 H NMR (400MHz, DMSO-d6): δ7.51-7.46(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.

[0599] Step 2. Synthesis of 2-(3-(3-bromobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (20-2)

[0600] To a stirred solution of 20-1 (1 g, 2.739 mmol) in anhydrous DCM (10 mL) was added chlorosulfonic acid (0.63 g, 5.48 mmol) at 0 ° C in an inert atmosphere and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and stirred for 5 to 10 min. The precipitated solid obtained was collected by filtration and dried in vacuo to provide 20-2 (1.02 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f:0.2), which was used in the next step without further purification. MS (ESI): for C 15 H 16 Calculated value for BrN3O4S2: 444.98; found: 446 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ7.52-7.45(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.

[0601] Step 3. Synthesis of 2-(3-(3-bromobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (20-3)

[0602] A stirring solution of 20-2 (1 g, 2.242 mmol) in POCl (10 mL) was allowed to stir 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 ammonia (10 mL) was added at 0 ° C while stirring was continued for another 12 h at room temperature. 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 provide 20-3 (0.60 g, 60.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5). MS (ESI): for C 15 H 17 BrN4O3S2 calculated value: 443.99; found value: 447.1[M+2] + . 1 HNMR (400MHz, DMSO-d6): δ7.55-7.50(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.

[0603] 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)

[0604] 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 K3PO4 (0.36 g, 1.692 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd (dppf) Cl2 (50 mg, 0.0677 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 ° C for 2 h. After the reaction was completed (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 obtained was purified by CombiFlash chromatography (eluted with 1 to 2% MeOH in DCM) to provide 172 (0.14 g, 45.6%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5).

[0605] Example 21. 2-(3-(1-(2',5'-difluoro-[1,1'-biphenyl]-3-yl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (174)

[0606]

[0607] Step 1. Synthesis of 1-(3-bromophenyl)ethan-1-ol (21-2)

[0608] At 0 ° C., under a nitrogen atmosphere, a stirred solution of 21-1 (5 g, 25.119 mmol) in methanol (35 mL) was added with a small portion of NaBH4 (1.43 g, 37.68 mmol) and then the reaction mixture was slowly warmed to room temperature and stirred for 3 h. After the reaction was completed (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 layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 21-2 (4.5 g, thick) as a yellow viscous solid, which can be used in the next step without further purification.

[0609] Step 2. Synthesis of 1-bromo-3-(1-bromoethyl)benzene (21-3)

[0610] Phosphorus tribromide (2.13 mL, 22.38 mmol) was added dropwise to a stirred solution of 21-2 (4.5 g, 22.38 mmol) in DCM (20 mL) at 0 ° C in an inert atmosphere and the reaction mixture was stirred for 4 h at the same temperature. After the reaction was completed (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 provide 21-3 (4 g, crude) as a light green solid, which was used in the next step without further purification. TLC: 10% EtOAc / heptane (R f :0.5).

[0611] Step 3. Synthesis of 1-(1-(3-bromophenyl)ethyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (21-4)

[0612] To a stirred solution of 2-2 (0.8 g, 4.060 mmol) in anhydrous DMF (8 mL) was added NaH (60% w / w in mineral oil, 0.24 g, 6.091 mmol) in a small portion at 0 ° C under a nitrogen atmosphere and the resulting reaction mixture was stirred for 15 min at the same temperature. To this reaction mixture was added 21-3 (1.6 g, 6.091 mmol) at 0 ° C and then the reaction mixture was slowly warmed to room temperature and stirred at 50 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 20 to 30% EtOAc in heptane) to provide 21-4 (1.2 g, 77.9%) as a yellow solid. TLC: 40% EtOAc / heptane (R f :0.5). MS (ESI): for C 16 H 18 BrN3OS calculated value: 379.04; found value: 379.9 [M+1] + .

[0613] Step 4. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (21-5)

[0614] To a stirred solution of 21-4 (1.2 g, 3.165 mmol) in anhydrous DCM (12 mL) was added chlorosulfonic acid (0.42 mL, 6.331 mmol) at 0 ° C in an inert atmosphere 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 obtained crude residue was purified by trituration with ether. The obtained solid was filtered off and dried in vacuo to provide 21-5 (0.8 g, crude) as a light brown solid. TLC: 50% EtOAc / heptane (R f :0.3). MS (ESI): for C 16 H 18 BrN3O4S2 calculated value: 458.99; found value: 461.7 [M+2] + .

[0615] Step 5. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonyl chloride (21-6)

[0616] A stirred solution of 21-5 (0.8 g, 1.742 mmol) in POCl (8 mL) was allowed to stir 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 afford 21-6 (0.7 g, crude) as an orange solid, which was used without further purification.

[0617] Step 6. Synthesis of 2-(3-(1-(3-bromophenyl)ethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (21-7)

[0618] Ammonia (1 mL) was added dropwise to a stirred solution of 21-6 (0.6 g 1.257 mmol) in THF (6 mL) at 0 ° C. The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluted with 20 to 50% EtOAc in heptane) to provide 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): for C 16 H 19 BrN4O3S2 calculated value: 458.01; found value: 460.7 [M+2] + .

[0619] 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)

[0620] To a stirred solution of 21-7 (0.15 g, 0.327 mmol) in 1,4-dioxane and water (2.5:0.5 mL) was added (2,5-difluorophenyl) boronic acid (0.13 g, 0.818 mmol) and K3PO4 (0.17 g, 0.818 mmol) and the reaction mixture was purged under nitrogen for 10 min. Pd(dppf)Cl2 (25 mg, 0.038 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 10 h. After the reaction was completed (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 provide 174 (80 mg) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0621] Example 22. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (5)

[0622]

[0623] Step 1. Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (5-2)

[0624] A mixture of compound 5-1 (6 g, 52.632 mmol) and 1-chloro-3-isocyanate propane (6.26 g, 52.632 mmol) in THF (60 mL) was heated at 70 ° C for 6 h. TBAB (1.7 g, 5.263 mmol) and K2CO3 (18.15 g, 131.58 mmol) were added portionwise to the resulting solution, the same temperature was maintained and stirring was continued at 70 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 60 to 70% EtOAc in heptane) to provide 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): for C8H 11 N3OS calculated value: 197.06; measured value: 198.17[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.30(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.

[0625] Step 2. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (5-3)

[0626] To a stirred solution of compound 5-2 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL) was added Int#5A (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol), followed by CuI (0.96 g, 5.076 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture was added 1,2-dimethylethylenediamine (0.9 g, 10.152 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 120 °C in a sealed tube for 24 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 (eluted with 30 to 40% EtOAc in heptane) to provide 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): for C 20 H 17 F2N3OS calculated value: 385.11; measured value: 385.90[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.61(d,J=7.8Hz,2H),7.54-7.35(m,4H),7.35-7.21(m,1H),6.7 0(s,1H),4.17(t,J=5.6Hz,2H),3.81(t,J=4.9Hz,2H),2.26(s,3H),2.24-2.21(m,2H)ppm.

[0627] 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)

[0628] To a stirred solution of compound 5-3 (4 g, 10.389 mmol) in anhydrous DCM (40 mL) was added chlorosulfonic acid (2.07 mL, 31.168 mmol) at 0 ° C in an inert atmosphere 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 obtained crude residue was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to provide the title compound 5-4 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2). MS (ESI): for C 20 H 17 F2N3O4S2 calculated value: 465.06; found value: 466[M+1] + .

[0629] Step 4. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (5)

[0630] A stirring solution of compound 5-4 (3.3 g, 7.096 mmol) in POCl (33 mL) was allowed to stir at 90 ° C for 5 h. 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 for another 12 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 100% EtOAc) to provide the desired product 5 (1.1 g, 44.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ7.65-7.59(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.

[0631] Step 5. Synthesis of 4'-bromo-2,5-difluoro-1,1'-biphenyl (Int.5A)

[0632] 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)boric 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 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad 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 provide the title compound Int.5A (2.3 g, 48.6%) as an off-white solid. TLC: 100% heptane (R f :0.5). 1 H NMR (400MHz, CDCl3): δ7.58 (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.

[0633] 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)

[0634]

[0635] Synthesis of 4-(3-bromo-2,5-difluorophenyl)-1H-pyrazole (23-2)

[0636] To a stirred solution of 1,3-dibromo-2,5-difluorobenzene (23-1) (1215 mg, 4.47 mmol) and (1H-pyrazole-4-yl) boronic acid (500 mg, 4.47 mmol) in DME (10 mL) was added water (4.00 mL), K2CO3 (1.853 g, 13.41 mmol) and Pd (dppfcl2) DCM (365 mg, 0.447 mmol) and purged with nitrogen for 10 min. The reaction mixture was heated at 80 ° C for 3 h. 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 on a rotary evaporator (bath temperature 45° C.) under reduced pressure to provide 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) 5μm), mobile phase A: 0.1% formic acid in H2O, mobile phase B: ACN, flow rate: 1.5ml / min).

[0637] Synthesis of 4-(3-bromo-2,5-difluorophenyl)-1-(difluoromethyl)-1H-pyrazole (23-3)

[0638] 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) was added diethyl (bromodifluoromethyl)phosphonate (0.275 mL, 1.544 mmol) and the reaction mixture was stirred at room temperature for 16 h. Upon 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 provide a crude product. The crude product obtained was purified by Isolera column chromatography technique using 230-400 silica gel, eluting in 20% ethyl acetate: petroleum ether. The combined pure fractions were concentrated on a rotary evaporator under reduced pressure to provide pure 4-(3-bromo-2,5-difluorophenyl)-1-(difluoromethyl)-1H-pyrazole (23-3) (20 mg, 0.062 mmol, 8% yield) as a light yellow liquid. LCMS: 2.044 min, 97.65%, 310.9 (M+H) +, (column: XBridge C18 (50x4.6 mm) 3.5 μm, mobile phase A: 0.1% TFA in H2O, mobile phase B: ACN, flow rate: 2.0 ml / min).

[0639] 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)

[0640] 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)tetrahydropyrimidine-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 min. The reaction mixture was heated at 80 ° C for 3 h. The reaction was monitored by LCMS. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2x5 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 (FA method) to afford 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.

[0641] Example 24: Synthesis of 2-(3-(4-(4,6-difluoropyridin-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (235)

[0642]

[0643] Synthesis of 2-(3-(4-(4,6-difluoropyridin-2-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (235)

[0644] To a stirred solution of compound 2-6 (0.18 g, 0.386 mmol) in 1,4-dioxane and water (4:1 mL) was added 2-bromo-4,6-difluoropyridine (50 mg, 0.257 mmol), followed by K3PO4 (0.10 g, 0.515 mmol) and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution was added PdCl2(dppf) (19 mg, 0.0257 mmol) under a nitrogen atmosphere and the reaction mixture was heated at 110 ° C for 16 h. After the reaction was completed (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 provide the title compound 235 (20 mg, 16.5%) as an off-white solid.

[0645] 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)

[0646]

[0647] Synthesis of 3-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-1-(4-bromophenyl)-1-((3-(hydroxymethyl)oxetane-3-yl)methyl)urea (25-1)

[0648] To a stirred solution of compound 13-1 (4 g, 9.259 mmol) in DMF (40 mL) was added CS2CO3 (7.54 g, 23.147 mmol) at 0°C, followed by (3-(bromomethyl)oxetane-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 the reaction was completed (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 to 50% EtOAc in heptane) to provide the title compound 25-1 (1 g, 20.2%) as a light yellow solid.

[0649] Synthesis of 6-(5-(phenylmethylthio)-4-methylthiazol-2-yl)-8-(4-bromophenyl)-2-oxa-6,8-diazaspiro[3.5]nonan-7-one (25-2)

[0650] Triphenylphosphine (0.66 g, 2.50 mmol) and DEAD (0.44 g, 2.50 mmol) were added to a stirred solution of compound 25-1 (0.9 g, 1.70 mmol) in toluene (10 mL) at 0 ° C. The resulting reaction mixture was slowly warmed to room temperature and stirred at 100 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 40 to 50% EtOAc in heptane) to provide the title compound 25-2 (0.55 g, 63%) as a light yellow solid.

[0651] Synthesis of 6-(5-(phenylmethylthio)-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)

[0652] 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 min. PdCl (dppf) (35 mg, 0.0484 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, then washed with brine. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by Combi Flash chromatography (eluted with 50 to 60% EtOAc in heptane) to provide the title compound 25-3 (0.11 g, 21.6%) as an off-white solid.

[0653] 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)

[0654] To a stirred solution of compound 25-3 (0.110 g, 0.200 mmol) in AcOH: H2O (3: 0.1 mL) was added N-chlorosuccinimide (93 mg, 0.701 mmol) and then the reaction mixture was stirred at room temperature for 30 min. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (1 mL) and ammonia (2 mL) was added at 0 ° C. and stirring was continued for another 1 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and filtered. The crude compound obtained was purified by Combi Flash chromatography (eluted with 70 to 80% EtOAc in heptane), followed by preparative HPLC to provide the title compound 339 (13 mg, 13%) as an off-white solid.

[0655] 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)

[0656]

[0657] Synthesis of ethyl (E)-3-ethoxy-2-(ethoxymethyl)acrylate (26-2)

[0658] Sodium ethoxide (9.3 g, 136.98 mmol) and ethyl formate (10 g, 136.98 mmol) were added to a stirred solution of compound 26-1 (10 g, 68.493 mmol) in toluene (120 mL) at 0 ° C under a nitrogen atmosphere, and the resulting reaction mixture was stirred for 2 h at the same temperature. Dimethyl sulfate (13 mL, 136.98 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 the reaction was completed (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound 26-2 (11 g, thick) as a yellow oil. TLC: 20% EtOAc / heptane (R f :0.2).

[0659] Synthesis of 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (26-3)

[0660] 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 h. The reaction mixture was concentrated to dryness under reduced pressure. The obtained crude residue was purified by trituration with ethanol. The obtained solid was filtered off and dried in vacuo to provide the title compound 26-3 (2.0 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.3), which was used in the next step without further purification.

[0661] Synthesis of 2-oxohexahydropyrimidine-5-carboxylic acid ethyl ester (26-4)

[0662] A solution of compound 26-3 (1.6 g, 9.090 mmol) in ethanol (50 mL) was loaded into an autoclave and the solution was purged for 10 min under a nitrogen atmosphere. 10% Pd / C (0.6 g) was added at room temperature under an inert atmosphere. The resulting reaction mixture was stirred for 16 h at 100 Psi under a hydrogen atmosphere at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated to dryness under reduced pressure to provide the title compound 26-4 (1.2 g, thick) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0663] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxohexahydropyrimidine-5-carboxylic acid ethyl ester (26-5)

[0664] 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 for 10 min under nitrogen. 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 h. After the reaction was completed (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 obtained was purified by CombiFlash chromatography (eluting with 60 to 80% EtOAc in heptane) to provide the title compound 26-5 (0.7 g, 28%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0665] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxylic acid ethyl ester (26-6)

[0666] To a stirred solution of compound 26-5 (0.7 g, 1.944 mmol) in toluene (12 mL) was added 2-bromo-4-methylthiazole (0.27 g, 1.555 mmol) and K2CO3 (0.64 g, 4.86 mmol) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (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 obtained was purified by CombiFlash chromatography (eluting with 10 to 40% EtOAc in heptane) to provide the title compound 26-6 (0.5 g, 62.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0667] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxamide (26-7)

[0668] A solution of compound 26-6 (0.2 g, 0.437 mmol) in 7M ammonia in methanol (10 mL) was heated at 70 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The obtained crude compound was purified by CombiFlash chromatography (eluted with 60 to 80% EtOAc in heptane) to provide the title compound 26-7 (0.14 g, 74.8%) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.5).

[0669] 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)

[0670] To a stirred solution of compound 26-7 (0.2 g, 0.467 mmol) in anhydrous DCM (5 mL) was added chlorosulfonic acid (0.1 g, 0.934 mmol) at 0 ° C in an inert atmosphere, 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 obtained crude residue was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to provide the title compound 26-8 (0.13 g, crude) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.3), which was used in the next step without further purification.

[0671] 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)

[0672] To a stirred solution of compound 26-8 (0.1 g, 0.196 mmol) in 1,2-dichloroethane (2 mL) was added POCl3 (1 mL) 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 provide the title compound 26-9 (0.1 g, crude) as a brown oil. TLC: 70% EtOAc in heptane (R f :0.5). This compound was used as is without further purification.

[0673] Synthesis of 2-(5-cyano-3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (360)

[0674] Ammonia (1 mL) was added dropwise to a stirred solution of compound 26-9 (0.1 g 0.196 mmol) in THF (2 mL) at 0 ° C. The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 2 h. After the reaction was completed (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 provide the title compound 360 (15 mg, 15.6%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0675] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methyl-5-(methylsulfonyl)thiazol-2-yl)-2-oxohexahydropyrimidine-5-carboxylic acid methyl ester (384)

[0676] To a stirred solution of compound 360 (0.2 g, 0.409 mmol) in MeOH:H2O (4:1 mL) was added H2SO4 (2 mL) and the resulting reaction mixture was heated at 100 ° C for 16 h. After the reaction was completed (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 obtained was purified by CombiFlash chromatography (eluted with 0 to 80% EtOAc in heptane) and then prepared by HPLC to provide the title compound 384 (0.15 g, 70.4%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0677] 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)

[0678] To a stirred solution of compound 384 (0.15 g, 0.287 mmol) in anhydrous THF (5 mL) was added methyl lithium solution (1.6 M in ether, 0.89 mL, 1.436 mmol) at -78 ° C under an argon atmosphere and the reaction mixture was stirred for 1 h at the same temperature. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layer was 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 produce 26-10. The preparative HPLC and SFC chiral separation of 26-10 provided compound 343 (0.13 g, 86.6%) and compound 344 as off-white solids, respectively. Stereochemistry was arbitrarily specified. TLC: 70% EtOAc / heptane (R f :0.5).

[0679] 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)

[0680]

[0681] Synthesis of 5-Hydroxytetrahydropyrimidin-2(1H)-one (27-2)

[0682] 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 was added diethyl carbonate (1.57 g, 133.33 mmol), 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 obtained crude residue was purified by trituration with DCM and stirred for 1 h. The obtained solid was filtered off and dried in vacuo to provide the title compound 27-2 (5 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2).

[0683] Synthesis of 5-((tert-butyldiphenylsilyl)oxy)tetrahydropyrimidin-2(1H)-one (27-3)

[0684] 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 in small portions and the resulting reaction mixture was stirred for 10 to 15 min at the same temperature. Tert-butyl (chloro) diphenylsilane (17.7 g, 64.654 mmol) was added to this reaction mixture at 0 ° C and then the reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluted with 40 to 50% EtOAc in heptane) to provide the title compound 27-3 (10 g, 65.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0685] Synthesis of 5-((tert-butyldimethylsilyl)oxy)-1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-4)

[0686] 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 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluted with 40 to 50% EtOAc in heptane) to provide the title compound 27-4 (1 g, 21.2%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0687] Synthesis of 5-((tert-butyldimethylsilyl)oxy)-1-(4-iodophenyl)-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-5)

[0688] 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 min. CuI (42 mg, 0.221 mmol) was added to the resulting reaction mixture under a nitrogen atmosphere. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 20 to 30% EtOAc in heptane) to provide the title compound 27-5 (1.0 g, 68.96%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0689] 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)

[0690] To a stirred solution of compound 27-5 (1 g, 1.531 mmol) in 1,4-dioxane and water (15:4 mL) was added (2,5-difluorophenyl) boronic acid (0.36 g, 2.296 mmol) and K3PO4 (0.811 g, 3.827 mmol) and the reaction mixture was purged under nitrogen for 10 min. PdCl2(dppf) (0.11 g, 0.153 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 110 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and 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 CombiFlash chromatography (eluted with 20 to 30% EtOAc in heptane) to provide the title compound 27-6 (0.7 g, 71.5%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0691] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-hydroxy-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-7)

[0692] Tetrabutylammonium fluoride (1M solution in THF, 0.572mL, 2.190mmol) was added dropwise to a stirred solution of compound 27-6 (0.7g, 1.095mmol) in anhydrous THF (10mL) at 0°C under a nitrogen atmosphere. The resulting reaction mixture was slowly warmed to room temperature and stirred for 2h. After the reaction was completed (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 (eluted with 20 to 30% EtOAc in heptane) to provide the title compound 27-7 (0.4g, 91.1%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0693] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methoxy-3-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (27-8)

[0694] To a stirred solution of compound 27-7 (0.4 g, 0.997 mmol) in THF (5 mL) was added NaH (60% w / w in mineral oil, 79.8 mg, 1.995 mmol) in a small portion at 0 ° C under a nitrogen atmosphere and the resulting reaction mixture was stirred for 5 to 10 min at the same temperature. Methyl iodide (0.28 g, 1.995 mmol) was added to this reaction mixture at 0 ° C and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed (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 crude compound was purified by CombiFlash chromatography (eluted with 20 to 30% EtOAc in heptane) to provide the title compound 27-8 (0.2 g, 48.3%) as an off-white solid. TLC: 30% EtOAc / heptane (R f :0.5).

[0695] 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)

[0696] To a stirred solution of compound 27-8 (0.15 g, 0.361 mmol) in anhydrous DCM (4 mL) was added chlorosulfonic acid (84 mg, 0.722 mmol) at 0 ° C in an inert atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The obtained crude residue was purified by trituration with ether. The obtained solid was filtered off and dried in vacuo to provide the title compound 27-9 (0.15 g, crude) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.3), which was used in the next step without further purification.

[0697] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methoxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (357)

[0698] A mixture of compound 27-9 (0.15 g, 0.303 mmol) and POCl3 (2 mL) was allowed to stir 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 ammonia (2 mL) was added at 0 ° C while stirring was continued for another 16 h at room temperature. 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 preparative HPLC to provide the title compound 357 (12 mg, 8%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0699] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-hydroxy-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (353)

[0700] To a stirred solution of 357 (0.32 g, 0.646 mmol) in DMF (1 mL) was added a boron tribromide solution (1.0 M in DCM, 10 mL, 10.343 mmol) at 0 ° C under a nitrogen atmosphere. The resulting reaction mixture was slowly warmed to room temperature and stirred at 100 ° C for 48 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluted with 2 to 5% MeOH in DCM) followed by preparative HPLC to provide the title compound 353 (10 mg, 3.2%) as an off-white solid. TLC: 5% MeOH / DCM (R f:0.3).

[0701] 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)

[0702]

[0703] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonic acid (28-1)

[0704] To a stirred solution of compound 18-1 (4 g, 10.389 mmol) in anhydrous DCM (40 mL) was added chlorosulfonic acid (2.07 mL, 31.168 mmol) at 0 ° C in an inert atmosphere 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 obtained crude residue was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to provide the title compound 28-1 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R f :0.2).

[0705] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonyl chloride (28-2)

[0706] A stirred solution of compound 28-1 (4 g, 8.602 mmol) in POCl3 (20 mL) was allowed to stir 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 afford the title compound 28-2 (3.5 g, crude) as a brown solid. TLC: 50% EtOAc in heptane (R f This compound was used as is in the next step without further purification.

[0707] 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)

[0708] DIPEA (0.65 mL, 3.726 mmol) was added to a stirred solution of compound 28-2 (0.6 g, 1.242 mmol) in THF (6 mL) at 0 ° C, followed by 2-aminoethane-1-ol (0.14 g, 1.863 mmol). The resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluted with 50 to 60% EtOAc in heptane) and then prepared by HPLC to provide the title compound 388 (16 mg, 2.5%) as an off-white solid. TLC: 50% EtOAc / heptane (R f :0.5).

[0709] 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)

[0710]

[0711] Synthesis of Sodium 2-(3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfinate (29-2)

[0712] At room temperature, the stirring solution of sodium sulfite (62.1mg, 0.483mmol) in water (10ml) is stirred for 10 minutes. Sodium bicarbonate (83mg, 0.966mmol) is added, and the resulting solution is stirred for 1h at 50°C. Compound 29-1 (300mg, 0.483mmol) is added portionwise to the solution and the reaction mixture is continued to be stirred for 16h at 50°C. After the reaction is completed, as monitored by TLC, the reaction mixture is concentrated under vacuum to remove solvent. Methanol (5ml) is added to the residue and stirred for 30 minutes. The solid formed is removed by filtration, and the filtrate is concentrated under vacuum to provide the sodium salt (300mg, 90%) of compound 29-2 as a yellow solid.

[0713] LCMS: 1.26min, 66.06%, 433.0[M+H] + , (column: Acquity BEH C18 (50x2.1 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.

[0714] Note: Observe the sulfonic acid mass by LCMS.

[0715] Synthesis of 1-(5-((difluoromethyl)sulfonyl)-4-methylthiazol-2-yl)-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (412)

[0716] Compound 29-2 (100 mg, 0.221 mmol) in acetonitrile (3 mL) was added to a stirred solution of KOH (247 mg, 4.41 mmol) in water (3.00 mL). The reaction mixture was then cooled to 0 to 5 ° C and stirred vigorously for 10 minutes and allowed to stir diethyl (bromodifluoromethyl)phosphonate (177 mg, 0.662 mmol) and the reaction mixture 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 saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (ABC method) to provide compound 412 (1.9 mg, 1.8%) as an off-white solid.

[0717] LCMS: 2.22min, 98.02%, 482.0 (M+H) + , (column: XBridge C8 (50x4.6 mm) 3.5 μm, mobile phase A: 0.1% TFA in H2O, mobile phase B: acetonitrile, flow rate: 2.0 ml / min)

[0718] HPLC: 6.86 min, 98.90%, (column: XBridge C8 (50x4.6 mm) 3.5 μm, mobile phase A: 5 mM ammonium acetate in H2O, mobile phase B: acetonitrile, flow rate: 2.0 ml / min)

[0719] 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)

[0720]

[0721] Synthesis of 1-(4-bromophenyl)-3-(3-chloropropyl)urea (30-2)

[0722] To a stirred solution of compound 30-1 (5 g, 28.089 mmol) in THF (80 mL) was added 1-chloro-3-isocyanate propane (5 g, 42.134 mmol) at 0 ° C under a nitrogen atmosphere 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 Na2SO4, filtered and concentrated under reduced pressure to provide the title compound 30-2 (6 g, crude) as an off-white solid, which was used in the next step without further purification.

[0723] Synthesis of 1-(4-bromophenyl)tetrahydropyrimidin-2(1H)-one (30-3)

[0724] To a stirred solution of compound 30-2 (6 g, 20.689 mmol) in acetonitrile (90 mL) was added KCO (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 the reaction was completed (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 NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluted with 70 to 80% EtOAc in heptane) to provide the title compound 30-3 (4 g, 76.9%) as an off-white solid.

[0725] Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)tetrahydropyrimidin-2(1H)-one (30-4)

[0726] To a stirred solution of compound 30-3 (2.7 g, 11.00 mmol) in 1,4-dioxane:HO (20:5 mL) was added (2,5-difluorophenyl)boric acid (2 g, 13.00 mmol), followed by KPO (6.7 g, 32 mmol) and the reaction mixture was purged under nitrogen for 10 min. PdCl (dppf) (0.81 g, 1.1 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluted with 70 to 80% EtOAc in heptane] to provide the title compound 30-4 (1 g, 33%) as an off-white solid.

[0727] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylic acid methyl ester (30-5)

[0728] Compound 7 (2.31 g, 10.41 mmol) was added to a stirred solution of compound 30-4 (2 g, 6.937 mmol) in 1,4-dioxane (40 mL), followed by CS2CO3 (5.65 g, 17.34 mmol) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 50 to 100% EtOAc in heptane) to afford the title compound 30-5 (1.55 g, 52%) as an off-white solid.

[0729] Synthesis of 5-bromo-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylic acid methyl ester (30-6)

[0730] N-bromosuccinimide (1.3 g, 7.00 mmol) was added to a stirred solution of compound 30-5 (1.5 g, 3.50 mmol) in DCM (30 mL). The resulting reaction mixture was heated at 55 ° C for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography (eluted with 40 to 50% EtOAc in heptane) to provide the title compound 30-6 (1.60 g, 90%) as an off-white solid.

[0731] Synthesis of 5-(phenylmethylthio)-2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-4-carboxylic acid methyl ester (30-7)

[0732] Phenylmethyl mercaptan (0.92 g, 7.4 mmol) was added to a stirred solution of compound 30-6 (1.5 g, 3.00 mmol) in 1,4-dioxane (25 mL), followed by DIPEA (1.2 g, 8.90 mmol) and the reaction mixture was purged under nitrogen for 10 min. 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 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, 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 CombiFlash chromatography (eluting with 60 to 70% EtOAc in heptane) to afford the title compound 30-7 (1.4 g, 86%) as a yellow solid.

[0733] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-5-sulfonylthiazole-4-carboxylic acid methyl ester (30-8)

[0734] To a stirred solution of compound 30-7 (1 g, 1.80 mmol) in AcOH:H2O (8:0.1 mL) was added N-chlorosuccinimide (0.75 g, 5.40 mmol) and then the reaction mixture was stirred at room temperature for 30 min. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (20 mL) and ammonia (10 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 ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and the title compound 30-8 (0.5 g, 54%) was provided as an off-white solid.

[0735] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(hydroxymethyl)thiazole-5-sulfonamide (440)

[0736] To a stirred solution of compound 30-8 (0.15 g, 0.295 mmol) in THF (4 mL) was added lithium borohydride (14 mg, 0.590 mmol) at 0 ° C under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 5 to 10 min and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to provide the title compound 440 (10 mg, 7%) as an off-white solid.

[0737] Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-(fluoromethyl)thiazole-5-sulfonamide (441)

[0738] DAST (0.21 g, 1.249 mmol) was added to a stirred solution of compound 440 (0.2 g, 0.416 mmol) in DCM (7 mL) at 0 ° C under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 5 to 10 min and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to provide the title compound 441 (10 mg, 4.9%) as an off-white solid.

[0739] Table 1 shows the structures and assay 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 of ordinary skill.

[0740] Table 1: Representative exemplary compounds of the present invention

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831] Bioassay data

[0832] Cell culture

[0833] Vero cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 100 units / mL penicillin and streptomycin. The cells were passaged 2 to 3 times per week to maintain sub-confluent density.

[0834] Determination

[0835] HSV-1 antiviral assay

[0836] Vero cells were plated at 2.5 × 10 per well. 3 Cells were seeded at a density of 100 cells / mL in a 96-well plate and allowed to attach overnight. After attachment, the medium was replaced with 50 uL infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL 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 standardized to 0.5% for all treatments. After compound addition, 80 TCID 50 50uL infection medium of HSV-1 was added to the cells and cultured at 37°C for 4 days. After culture, the plate was equilibrated to room temperature, the medium was removed, and 60 aliquots of 1:1 diluted cell titer glow and phosphate buffered saline were added to the cells. After 5 minutes of culture, cell viability was quantified by measuring brightness using a Tecan Infinite M1000 Pro plate reader.

[0837] HSV-2 antiviral assay

[0838] Vero cells were plated at 1.0 × 10 4Cells were seeded at a density of 100 cells / mL in a 96-well plate and allowed to attach overnight. After attachment, the medium was replaced with 50 uL infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). Compounds were then added to the cultures using a Tecan D300e digital dispenser using 8-point 3-fold dilutions. DMSO concentrations were standardized to 0.5% for all treatments. After compound addition, a 160 TCID 50 50uL infection medium of HSV-2G strain was added to the cells and cultured for 5 days at 37°C. After culture, 10μL / well of WST-8 colorimetric reagent was added and the plate was cultured for 3 hours at 37°C. After culture, cell viability was quantified by measuring absorbance at 460nm and 620nm using a Tecan Infinite M1000 Pro plate reader.

[0839] Table 2 provides assay data for exemplary compounds of the invention grouped within the following ranges: A indicates EC 50 <100nM; B indicates EC 50 ≥100 to <1,000 nM; C indicates EC 50 ≥1,000 to <5,000 nM; NA indicates not available.

[0840] Table 2. Assay data for exemplary compounds of the invention.

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855] It should be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the presently disclosed subject matter.In addition, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

[0856] All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the purposes of the teachings of such references.

[0857] Test compounds used in the experiments described herein were employed in free or salt form.

[0858] The specific response observed may vary depending upon or upon the particular active compound selected or the presence or absence of carrier and the type of formulation and mode of administration employed, and such expected variations or differences in results are contemplated from the practice of the present disclosure.

[0859] Although specific embodiments of the present disclosure are described and explained 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 gist of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: yes Select from the group consisting of: X 2 and X 4 independently selected from the group consisting of O and S; X 5 is CH2, CF2, O, S or NR y , L is L 1 is a key; or when yes When L 1 is -CH2-; R a , R b , R c , R d , R e , R f , R g and R h are independently selected from the group consisting of: hydrogen, halogen, 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, C 2-4 Alkynyl, halide C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, and C 1-4 Alkoxy; or two R groups together with the carbon atom to which they are attached form a C 3-6 Monocyclic alkyl, Group; R n and R m Each occurrence is independently selected from hydrogen and C 1-4 The group consisting of alkyl groups; R y It is hydrogen, C 1-4 Alkyl or acetyl; R 1 yes R 2 is hydrogen, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halide C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, or halogen C 1-4 Alkoxy; R 4 Each occurrence is independently selected from the group consisting of: halo, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, optionally through hydroxyl C 1-3 Alkyl substituted C 2-4 alkynyl, cyclopropyl optionally substituted by halogen or cyano, and R 4b , the constraint is that there is only one R 4 The group can be R 4b ; R 4a It is hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl and hydroxyl C 1-4 alkyl; R 4b Select from the group consisting of: R 7 and R 8 are independently selected from the group consisting of: hydrogen, OH, acetyl, C 1-10 Alkyl, halogen C 1-10 Alkyl, hydroxyl C 1-10 Alkyl, C 1-4 Alkoxy C 1-10 Alkyl, C 3-6 monocyclic alkyl, phenyl, pyridyl or indolyl; or R 7 and R 8 together with the N atom to which it is attached, forms an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl, wherein the aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with halo, CN or OH; R 7a and R 8a independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Monocyclic alkyl, or R 7a and R 8a Together with the N atom to which it is attached, it forms an aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, morpholinyl or thiomorpholinyl group; R 9 and R 9a Independently selected from C 1-4 Alkyl and halogen C 1-4 The group consisting of alkyl groups; R 10 and R 10a independently selected from hydrogen and C 1-4 The group consisting of alkyl groups; R 11 Independently selected from the group consisting of: halogen, CN, OH, NR n R m , C 1-4 Alkyl, halogen C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, and C 3-6 Monocyclic alkyl; R 11a It is hydrogen, C 1-4 Alkyl, halogen C 1-4 Alkyl, and hydroxyl 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; and v and y are independently selected from the group consisting of 0, 1, 2 and 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes and Select from the group consisting of:

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: yes and yes 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes and Select from the group consisting of:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes and Select from the group consisting of:

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: yes and yes 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: L is 8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein: L is 9. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: L is 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein: L is 11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: R 2 It is H, Cl, F, CH3 or CF3.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein: R 2 It is CH3.

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 16. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 18. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 20. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 21. The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes 22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 3 Each occurrence of is halo, 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. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein: R 4 Each occurrence is independently selected from the group consisting of halo, CN, methyl, CHF2, CF3, ethynyl, and cyclopropyl.

25. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein: R 4 Each occurrence is independently selected from halo.

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 method for treating or preventing HSV infection in a subject in need thereof, the method comprising: A therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof is administered to the subject.

28. A method for treating or preventing HSV infection in a subject in need thereof, the method comprising: Administering a therapeutically effective amount of the pharmaceutical composition of claim 26 to the subject.

29. The method of claim 27 or 28, wherein the infection is an HSV-1 infection.

30. The method of claim 27 or 28, wherein the infection is an HSV-2 infection.

31. A compound according to any one of claims 1 to 25 for use as a medicament.

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